Enhanced Infiltration of Central Memory T Cells to the Lung Tissue during Allergic Lung Inflammation

2021 ◽  
pp. 1-15
Author(s):  
Mashael Alabed ◽  
Asma Sultana Shaik ◽  
Narjes Saheb Sharif-Askari ◽  
Fatemeh Saheb Sharif-Askari ◽  
Shirin Hafezi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lung Tissue ◽  
Lung Inflammation ◽  
Inflammatory Responses ◽  
Memory T Cells ◽  
Central Memory ◽  
Effector Memory ◽  
Differential Distribution ◽  
Allergic Lung Inflammation

Memory T cells play a central role in regulating inflammatory responses during asthma. However, tissue distribution of effector memory (T<sub>EM</sub>) and central memory (T<sub>CM</sub>) T-cell subtypes, their differentiation, and their contribution to the persistence of lung tissue inflammation during asthma are not well understood. Interestingly, an increase in survival and persistence of memory T cells was reported in asthmatic lungs, which may suggest a shift toward the more persistent T<sub>CM</sub> phenotype. In this report, we investigated the differential distribution of memory T-cell subtypes during allergic lung inflammation and the mechanism regulating that. Using an OVA-sensitized asthma mouse model, we observed a significant increase in the frequency of T<sub>CM</sub> cells in inflamed lungs compared to healthy controls. Interestingly, adoptive transfer techniques confirmed substantial infiltration of T<sub>CM</sub> cells to lung tissues during allergic airway inflammation. Expression levels of T<sub>CM</sub> homing receptors, CD34 and GlyCAM-1, were also significantly upregulated in the lung tissues of OVA-sensitized mice, which may facilitate the increased T<sub>CM</sub> infiltration into inflamed lungs. Moreover, a substantial increase in the relative expression of T<sub>CM</sub> profile-associated genes (EOMES, BCL-6, ID3, TCF-7, BCL-2, BIM, and BMI-1) was noted for T<sub>EM</sub> cells during lung inflammation, suggesting a shift for T<sub>EM</sub> into the T<sub>CM</sub> state. To our knowledge, this is the first study to report an increased infiltration of T<sub>CM</sub> cells into inflamed lung tissues and to suggest differentiation of T<sub>EM</sub> to T<sub>CM</sub> cells in these tissues. Therapeutic interference at T<sub>CM</sub> infiltration or differentiations could constitute an alternative treatment approach for lung inflammation.

Circulating Memory T Cells Isolated from Hodgkin Lymphoma Patients Display Evidence of Exhaustion and Chronic Activation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4400-4400
Author(s):  
Catherine S. Diefenbach ◽  
Bruce G. Raphael ◽  
Kenneth B. Hymes ◽  
Tibor Moskovits ◽  
David Kaminetzky ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Memory T Cells ◽  
Central Memory ◽  
Effector Memory ◽  
T Cell Exhaustion ◽  
Differentiation Markers ◽  
Cell Markers ◽  
Cell Exhaustion ◽  
Central Memory T Cells

Abstract Background: In Hodgkin lymphoma (HL) the malignant Hodgkin Reed-Sternberg (HRS) cells comprise only a small fraction of the total cellular tumor population. These HRS cells orchestrate an inflammatory microenvironment of reactive cells that propagate a permissive milieu for HL growth, contributing to an ineffective local anti-tumor immune response. The peritumoral CD4 and CD8 T cells in HL patients show high expression of the receptor programmed death-1 (PD-1), involved in the functional impairment and “exhaustion” of T cells. Growing data suggests that this HL-mediated immune suppression may have effects that extend beyond the tumor microenvironment. High systemic levels of inflammatory cytokines and chemokines in HL patients has been reported. We characterized the systemic immune profile of HL patients with both newly diagnosed (ND) and relapsed (R) disease. Methods: Informed consent for correlative blood testing was obtained from patients with ND (n=8) or R (n=5) HL treated at the NYU Perlmutter Cancer Center or NY Presbyterian/Weil Cornell since January of 2013. Blood samples were drawn pre-treatment, and at sequential timepoints during and after therapy. Peripheral blood mononuclear cells (PBMC) were isolated using Ficoll separation method and cells were frozen for subsequent analysis. The frozen PBMC were then stained with fluorescent-conjugated antibodies against T cell surface molecules in 10-color FACS analysis. The analyses were performed after gating live cells for CD4, CD8 and memory and effector T cell markers. Patient samples were compared to normal controls matched for age and sex (n=18). Results: The median HL patient age was 32 (22-72), and 8 subjects were male. All ND HL patients were treated with ABVD (range 4-6 cycles) +/- consolidative radiation; R patients had median of 3 prior therapies. One patient out of 5 had prior autologous stem cell transplant (SCT), and 1 had prior allogeneic SCT, but was not on immunosuppression. Eight patients (6ND, 2R) responded to therapy (8 CR); 5 patients (1ND, 4R) progressed on therapy or had stable disease. HL patients displayed a high frequency of the exhaustion marker PD-1 on CD4 central memory T cells (CD4+CD45RO+CD27+) compared to normal matched controls (NC): mean 41, standard error (SE) 4.8 for HL patients vs. mean 22.2, SE 1.3 for NC (p = 0.0002) (Figure 1A). PD-1 expression was similarly elevated on CD8 central memory T cells (CD8+CD45RO+CD27+) of HL patients: mean 55, SE 3.3 vs. NC: mean 40, SE 3.3 (p = 0.003) (Figure 1B). HL patients also displayed an increased frequency of PD-1 expression on CD27 negative CD4 effector T cells: mean 43, SE 4, vs. NC: mean 28.5, SE 2.4 (p = 0.003) (Figure 2). In 4 of the HL patients who responded to therapy, PD-1 expression on central memory CD4+ cells declined after therapy: mean 30.1 vs. mean increase of +2.67 in 3 patients who progressed on therapy (p< 0.009). A higher number of subjects in prospective analysis is underway, to confirm whether a response to therapy may be correlated with a reversal of the suppressed phenotype of T cells in these patients. Conclusion: HL patients have evidence of chronic activation/exhaustion in their central memory and effector T cells, suggesting that ineffective immune clearance of the HRS cells may be a systemic rather than local phenomenon. In patients with progressive disease for whom this phenotype persists it is worthy of investigation whether this immune dysfunction is a cause or consequence of resistance to therapy. This may be rationale for immune targeted therapy in patients with relapsed or resistant disease. Figure 1. Evidence for increased levels of T cell exhaustion in central memory T cells of HL patients. PBMC were stained with specific fluorescent conjugated antibodies against T cell markers (CD3, CD4, CD8) together with differentiation markers (CD45RO, CD27) and PD1 and analyzed using FACS (LSR-II). The proportion of PD1+ T cells were determined in: A) CD4+CD45RO+CD27+ and B) CD8+CD45RO+CD27+ T cells. Figure 1. Evidence for increased levels of T cell exhaustion in central memory T cells of HL patients. PBMC were stained with specific fluorescent conjugated antibodies against T cell markers (CD3, CD4, CD8) together with differentiation markers (CD45RO, CD27) and PD1 and analyzed using FACS (LSR-II). The proportion of PD1+ T cells were determined in: A) CD4+CD45RO+CD27+ and B) CD8+CD45RO+CD27+ T cells. Figure 2. Evidence for increased levels of T cell exhaustion in effector memory CD 4+ T cells of HL patients. PBMC were stained with specific fluorescent conjugated antibodies against T cell markers (CD3, CD4) together with differentiation markers (CD45RO, CD27) and PD1 and analyzed using FACS (LSR-II). The proportion of PD1+ T cells was determined in CD4+RO+CD27- T cells Figure 2. Evidence for increased levels of T cell exhaustion in effector memory CD 4+ T cells of HL patients. PBMC were stained with specific fluorescent conjugated antibodies against T cell markers (CD3, CD4) together with differentiation markers (CD45RO, CD27) and PD1 and analyzed using FACS (LSR-II). The proportion of PD1+ T cells was determined in CD4+RO+CD27- T cells Figure 3 Figure 3. Disclosures No relevant conflicts of interest to declare.

CXCR3 Is Required for the Efficient Recruitment of Bone Marrow-Resident Memory T Cells to Inflamed Tissues,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3242-3242
Author(s):  
Robbert van der Voort ◽  
Claudia Brandao ◽  
Thomas J. Volman ◽  
Viviènne Verweij ◽  
Klaas van Gisbergen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Cd8 T Cells ◽  
Memory T Cells ◽  
Central Memory ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Memory T Cell

Abstract Abstract 3242 Although the importance of the bone marrow (BM) in hematopoiesis is well known, its function in adaptive immune responses has only recently been acknowledged. Currently it is known that the BM contains fully functional CD4+ and CD8+ T cells that can engage in both primary and secondary immune responses. Interestingly, most of these T cells belong to the memory T cell lineage, identifying the BM as one of the largest memory T cell reservoirs in the body. Since not much is known about the trafficking of BM T cells, we compared the homing phenotype and function of T cell subsets in the BM, blood, spleen and peripheral lymph nodes (pLN). In addition, we determined the expression of chemokine mRNA and protein levels in the BM and other lymphoid organs. We confirmed that at least 80% of the CD4+ and 60% of the CD8+ BM T cells have a memory phenotype, and that most CD4+ T cells belong to the effector memory lineage, while the CD8+ population predominantly consists of central memory T cells. Most BM T cells expressed the chemokine receptor CXCR3, the adhesion molecules P-selectin glycoprotein ligand 1 and VLA-4, and increased levels of CD44 and LFA-1, as compared to T cells from the spleen. In addition, L-selectin was absent from most CD4+ BM T cells, but present on virtually all CD8+ T cells. Notably, the percentage of CXCR3+ T cells within the effector memory and central memory subsets from BM was higher than within the same subsets from pLN. Furthermore, BM contained significant mRNA levels of the CXCR3 ligands CXCL9, CXCL10 and CXCL11. An in vivo migration assay using a mixture of fluorescent-labeled T cells from CXCR3-deficient mice and control mice indicated however that during homeostasis CXCR3 does not play a major role in BM entry or retention. These data suggest that CXCR3 expressed by memory T cells is rather involved in BM exit, than in BM entry. Indeed, we observed that, as compared to control mice, CXCR3−/− mice contained significantly more CD4+ and CD8+ T cells in their BM. Additional in vitro assays demonstrated that CD4+ and CD8+ BM T cells migrated vigorously in response to CXCL9 and CXCL10, generally released in high concentrations during inflammation. Finally, we demonstrate that CXCR3−/− effector/effector memory T cells, but not wild type T cells, accumulate in the BM of mice infected with lymphocytic choriomeningitis virus. Altogether, these data demonstrate that the BM is a major reservoir of memory T cells that employ CXCR3 to quickly respond to chemotactic signals from inflamed tissues. Disclosures: No relevant conflicts of interest to declare.

A Comparison of Human CMVpp65-Specific Central Memory and Effector Memory CD8 T-Cells When Stimulated in-Vivo with IL-2 or IL-15/IL-15Rα Complex in a Murine Xenograft Model of Adoptive Cell Therapy

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4805-4805
Author(s):  
Tzu-Yun Kuo ◽  
Aisha Hasan ◽  
Richard J O'Reilly
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Adoptive Immunotherapy ◽  
Memory T Cells ◽  
Cd8 T Cell ◽  
Central Memory ◽  
Effector Memory ◽  
Cell Clones

Abstract Initial clinical trials of adoptive immunotherapy have shown that the efficacy of adoptively transferred T-cells in man is often limited by the failure of cultured T cells, particularly cloned CD8 T cells, to persist in vivo. These studies demonstrated that the transferred T cells induced only transient responses and that persistence of the transferred T-cell clonotypes correlated with disease regression. A previous study suggested that CMV virus-specific CD8 T cell clones derived from central memory T cells (TCM), but not effector memory T cells (TEM), persisted long-term in non-human primates. On the other hand, another study comparing TCM and TEM derived SIV virus specific CD8 T-cell clones that were adoptively transferred in non-human primates demonstrated limited persistence of both TCM and TEM derived transferred T cells, and failed to show any difference between the two cell types. Because of these conflicting data, we have reexamed the persistence of adoptively transferred viral antigen specific T-cells derived from TCM and TEM population. Accordingly, we developed a NOG mouse model for studying the ability of human CMVpp65-specific T cells derived from central memory and effector memory populations to migrate to and accumulate in human tumor xenografts expressing CMVpp65, to alter the growth of these tumors and to persist in the tumors. This model also allows us to test immunomodulating agents and their ability to enhance targeted T-cell accumulations, antitumor activity and persistence. We analyzed CMVpp65-specific CD8 T cells derived from TCM and TEM precursors in vitro and in vivo. To tract the T-cells in vivo, we transduced membrane-bound Gaussia luciferase into TCM and TEM populations and monitored T cell trafficking by in vivo bioluminescence. Contrary to expectation, our results initially showed no differences between TCM and TEM derived CMVpp65-specific T-cell in mice co-treated with IL-2 in the time to accumulation, ultimate level of accumulation, degree of CMVpp65+ tumor regression or T-cell persistence. However, in mice cotreated with IL-15/IL-15Rα complex, both TCM and TEM exhibited more sustained engraftment and more prolonged accumulation in both the targeted tumor and in the marrow. In mice treated with IL-15/IL-15Rα, TCM and TEM derived T cells showed a similar effector memory phenotype and a similar level of regression of tumor growth. Thus, adoptive transfer of CMVpp65 specific TCM or TEM when combined with IL-15/IL-15Rα complex may support better persistence of antigen-specific T-cells following adoptive immunotherapy. Studies comparing IL-15/IL-15Rα complex with IL-15 alone are in progress. Disclosures No relevant conflicts of interest to declare.

P1138FLOW CYTOMETRIC ANALYSIS ON LYMPHOCYTE SUBSETS APPEARED IN PERITONEAL DIALYSIS EFFLUENT IN RELATION WITH PERITONEAL FUNCTION

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Atsuki Ohashi ◽  
Madoka Kondo ◽  
Fumitaka Ihara ◽  
Noriyuki Toshima ◽  
Yoshitatsu Ohara ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Memory T Cells ◽  
Central Memory ◽  
Effector Memory ◽  
Creatinine Ratio ◽  
Change Rate ◽  
Memory T Cell ◽  
Naïve T Cell ◽  
Naive T Cell

Abstract Background and Aims We previously reported that an increase of lymphocytes in peritoneal dialysis (PD) effluent was correlated with risk of encapsulating peritoneal sclerosis (EPS). In the present study, we analyzed subsets of lymphocytes in PD effluent by flow cytometry and evaluated their changes every six month to elucidate the etiological background of peritoneal dysfunction. Method We enrolled patients who started PD between 2006 and 2017, and of whom the data for PET and flow cytometric analysis was available at least for three consecutive times with an interval of six months. We excluded the patients who experienced PD peritonitis during the observation period. Consequently, the levels and changes of lymphocyte subset, such as CD4+/CD8+ naïve T cell (CCR7+/CD45RA+), CD4+/CD8+ central memory T cell (CCR7+/CD45RA-), CD4+/CD8+ effector memory T cell (CCR7-/CD45RA-), CD4+/CD8+ terminally differentiated effector memory T cell (CCR7-/CD45RA+), D/P creatinine ratio, FSC ratio of mesothelial cells and lymphocytes (a possible indicator for mesothelial cell size) were analysed in 23 patients over one year. Results We evaluated whether the observed variables on the first evaluation (six months after initiation of PD) affected the changes of D/P creatinine and FSC ratio over one year by a simple linear regression analysis. In the examined variables, only a fraction of CD8+ central memory T cell was significantly correlated with the change rate of D/P creatinine ratio (β=1.47, p=0.001, adjusted R2=0.379). We also evaluated whether the change rate of observed variables was correlated with the change rate of D/P creatinine and FSC ratio by a simple linear regression analysis. A fraction of CD8+ naïve T cell or CD8+ central memory cell was negatively correlated with the change rate of D/P creatinine ratio (naïve T cell; β=-0.058, p=0.022, adjusted R2=0.188, central memory T cell; β=-0.096, p=0.046, adjusted R2=0.137). The change rate of CD8+ effector memory T cell was not significantly correlated with the change rate of D/P creatinine ratio (β=0.172, p=0.096, adjusted R2=0.085). However, the change rate of D/P creatinine ratio tends to be higher in accordance with the increased change rate of CD8+ effector memory T cell by One way ANOVA, where the change rate was divided into three groups in descending order (p=0.0796) (Fig.1). Besides, the change rate of CD8+ effector memory T cell tends to be higher in accordance with the increased fraction of CD8+ central memory T cell at the first evaluation by Kruskall-Wallis test, where the change rate was divided into three groups in descending order (p=0.169) (Fig.2). Conclusion A decrease in the fraction of CD8+ naïve or central memory T cell was significantly correlated with the increase of D/P creatinine ratio. An Increase in the fraction of CD8+ effector memory T cell was also possibly correlated with the increase of D/P creatinine ratio, although it was not statistically significant (p=0.096). An initial fraction of CD8+ central memory T cell was significantly correlated with the change rate of D/P creatinine ratio. From these results, central memory T cells and naïve T cells at an initial stage may be transformed into effector memory T cells by repeated exposure to unknown antigens derived from PD solution and these effector memory T cells may damage the peritoneum to increase D/P creatinine ratio. An initial higher fraction of CD8+ central memory T cell suggested an acceleration in the transformation into CD8+ effector memory T cell.

scholarly journals Effect of Cyclophosphamide Treatment on Central and Effector Memory T Cells in Mice

2018 ◽  
Vol 37 (5) ◽  
pp. 373-382 ◽  
Author(s):  
Marcin Włodarczyk ◽  
Elżbieta Ograczyk ◽  
Magdalena Kowalewicz-Kulbat ◽  
Magdalena Druszczyńska ◽  
Wiesława Rudnicka ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Memory T Cells ◽  
Immunosuppressive Agent ◽  
Central Memory ◽  
Effector Memory ◽  
Memory Cells ◽  
Memory T Cell ◽  
Effector Memory T Cells ◽  
The Impact

Immunological memory is a key feature of adaptive immunity. It provides the organism with long-lived and robust protection against infection. The important question is whether cyclophosphamide (CP), as immunosuppressive agent used in cancer therapy and in some autoimmune diseases, may act on the memory T-cell population. We investigated the effect of CP on the percentage of central memory T cells (TCM) and effector memory T cells (TEM) in the mouse model of CP-induced immunosuppression (8-10-week-old male C57BL/6 mice CP treated for 7 days at the daily dose of 50 μg/g body weight [bw], manifested the best immunosuppression status, as compared to lower doses of CP: 10 or 20 μg/g bw). The CP induced a significant decrease in the percentage of CD8+ (TCM), compared to nonimmunosuppressed mice. This effect was not observed in the case of CD4+ TCM population. The percentage of gated TEM with CD4 and CD8 phenotype was significantly decreased in CP-treated mice, as compared to the control ones. Taken together, the above data indicate that CP-induced immunosuppression in mice leads to a reduction in the abundance of central memory cells possessing preferentially CD8+ phenotype as well as to a reduction in the percentage of effector memory cells (splenocytes both CD4+ and CD8+), compared to the cells from nonimmunosuppressed mice. These findings in mice described in this article may contribute to the understanding of the complexity of the immunological responses in humans and extend research on the impact of the CP model of immunosuppression in mice and memory T-cell populations.

scholarly journals Revisiting CD8 T-cell ‘Memory Inflation’: New Insights with Implications for Cytomegaloviruses as Vaccine Vectors

Vaccines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 402
Author(s):  
Rafaela Holtappels ◽  
Kirsten Freitag ◽  
Angelique Renzaho ◽  
Sara Becker ◽  
Niels A.W. Lemmermann ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Memory T Cells ◽  
Cd8 T Cell ◽  
Central Memory ◽  
Productive Infection ◽  
Effector Memory ◽  
Cmv Infection ◽  
Memory Inflation ◽  
Effector Memory T Cells

Murine models of cytomegalovirus (CMV) infection have revealed an exceptional kinetics of the immune response. After resolution of productive infection, transient contraction of the viral epitope-specific CD8 T-cell pool was found to be followed by a pool expansion specific for certain viral epitopes during non-productive ‘latent’ infection. This phenomenon, known as ‘memory inflation’ (MI), was found to be based on inflationary KLRG1+CD62L− effector-memory T cells (iTEM) that depend on repetitive restimulation. MI gained substantial interest for employing CMV as vaccine vector by replacing MI-driving CMV epitopes with foreign epitopes for generating high numbers of protective memory cells specific for unrelated pathogens. The concept of an MI-driving CMV vector is questioned by human studies disputing MI in humans. A bias towards MI in experimental models may have resulted from systemic infection. We have here studied local murine CMV infection as a route that is more closely matching routine human vaccine application. Notably, KLRG1−CD62L+ central memory T cells (TCM) and conventional KLRG1−CD62L− effector memory T cells (cTEM) were found to expand, associated with ‘avidity maturation’, whereas the pool size of iTEM steadily declined over time. The establishment of high avidity CD8 T-cell central memory encourages one to pursue the concept of CMV vector-based vaccines.

scholarly journals Vaccines Based on Novel Adeno-Associated Virus Vectors Elicit Aberrant CD8+ T-Cell Responses in Mice

2007 ◽  
Vol 81 (21) ◽  
pp. 11840-11849 ◽  
Author(s):  
Jianping Lin ◽  
Yan Zhi ◽  
Lauren Mays ◽  
James M. Wilson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Inflammatory Responses ◽  
Interleukin 2 ◽  
T Cell Response ◽  
Central Memory ◽  
Effector Memory ◽  
Necrosis Factor Alpha ◽  
Effector Response

ABSTRACT We recently discovered an expanded family of adeno-associated viruses (AAVs) that show promise as improved gene therapy vectors. In this study we evaluated the potential of vectors based on several of these novel AAVs as vaccine carriers for human immunodeficiency virus type 1 Gag. Studies with mice indicated that vectors based on AAV type 7 (AAV7), AAV8, and AAV9 demonstrate improved immunogenicity in terms of Gag CD8+ T-cell and Gag antibody responses. The quality of these antigen-specific responses was evaluated in detail for AAV2/8 vectors and compared to results with an adenovirus vector expressing Gag (AdC7). AAV2/8 produced a vibrant CD8+ T-cell effector response characterized by coexpression of gamma interferon and tumor necrosis factor alpha as well as in vivo cytolytic activity. No CD8+ T-cell response generated by any of the AAVs was effectively boosted with AdC7, a result consistent with the finding of a relative lack of cells expressing interleukin-2 (IL-2) or a central memory phenotype at 3 months after the prime. The primary response to an AdC7 vaccine differed from that generated by AAVs in that the peak effector response evolved into populations of Gag-specific T cells expressing high levels of cytokines, including IL-2, and with effector memory and central memory phenotypes. A number of mechanisms could be considered to explain the aberrant activation of CD8+ T cells by AAV, including insufficient inflammatory responses, CD4 help, and/or chronic antigen expression and T-cell exhaustion. Interestingly, the B-cell response to AAV-encoded Gag was quite vibrant and easily boosted with AdC7.

Imatinib Mesylate Has a Stage-Specific Inhibitory Role in Generation of CD26highCD8+ Central Memory T Cells in Vitro and in Vivo.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3243-3243
Author(s):  
Kazuaki Yokoyama ◽  
Tokiko Nagamura-Inoue ◽  
Shin Nakayama ◽  
Ikuo Ishige ◽  
Kazuo Ogami ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Memory T Cells ◽  
Central Memory ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Short Term ◽  
Central Memory T Cells

Abstract CD26 is a transmembrane glycoprotein with intrinsic dipeptidyl peptidase IV (DPPIV) activity as well as costimulatory activity of mitotic signals triggered by the CD3/TCR complex. Based on the expression level of CD26, CD4+ and CD8+ T cells can be divided into 3 (high/intermediate/low or negative) subsets. The significance of CD26 has been studied mainly on CD4+ T cells, and CD26highCD4+ T cells are considered to represent effector memory T cells of a typical Th1 phenotype producing IL2 and IFNg. Furthermore, we reported a significant decrease of this subset in CML patients under imatinib therapy in comparison to those under IFNa therapy and normal volunteers. In contrast, the role of each subset of CD8+ T cells has not yet been clarified. Multi-parameter flow cytometry analysis was performed to characterize CD8+ T cells differentially expressing CD26 in combination with intracellular detection of effector molecules such as perforin (P) and granzyme B (Gr). The capacity to secrete effector cytokines such as IFNg following short-term stimulation was also assessed. As a result, according to the expression level of CD26, we could clearly categorize CD8+ T cells as follows: CD26highCD8+ T cells are defined as central memory T cells which has a phenotype of CD45RO+CD28+CD27+ IFNg+Gr−P+/−, CD26intCD8+ T cells as naïve T cells of CD45ROCD28+ CD27+ IFNg−Gr−P−, and CD26lowCD8+ T cells as effector memory/effector T cells of CD45RO−/+ CD28−CD27−IFNg++Gr++P++, respectively. We next investigated the effects of imatinib on 3 distinct subsets during CD8+ T cell differentiation program. Peripheral blood mononuclear cells were primed with anti-CD3/CD28 MAb and subjected to the grading doses of imatinib for short term culture, followed by flow cytometory. CFSE labeling was used for monitoring cell proliferation. Intriguingly, we found that imatinib dose-dependently inhibits activation, cytokine production and proliferation of CD26highCD8+ central memory T cell subsets in a differentiation stage-specific manner. Finally, we compared the absolute number of peripheral blood CD26highCD8+ T cell subsets between 20 patients with CML in imatinib-induced CCR and 20 normal volunteers, clearly indicating a significant decrease of this subset in CML patients (22.30/ml vs 45.60/ml, p<0.01). The present study offers another evidence for immunomodulatory effects of imatinib or the critical role of Abl (-related) kinase in T cell development, and draws special attention to susceptibility to viral infection of CML patients under long-term imatinib therapy. Figure Figure

scholarly journals Sézary syndrome and mycosis fungoides arise from distinct T-cell subsets: a biologic rationale for their distinct clinical behaviors

Blood ◽  
2010 ◽  
Vol 116 (5) ◽  
pp. 767-771 ◽  
Author(s):  
James J. Campbell ◽  
Rachael A. Clark ◽  
Rei Watanabe ◽  
Thomas S. Kupper
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mycosis Fungoides ◽  
Memory T Cells ◽  
Central Memory ◽  
Effector Memory ◽  
Sézary Syndrome ◽  
Sezary Syndrome ◽  
Central Memory T Cells ◽  
Effector Memory T Cells

Abstract Cutaneous T-cell lymphoma (CTCL) encompasses leukemic variants (L-CTCL) such as Sézary syndrome (SS) and primarily cutaneous variants such as mycosis fungoides (MF). To clarify the relationship between these clinically disparate presentations, we studied the phenotype of T cells from L-CTCL and MF. Clonal malignant T cells from the blood of L-CTCL patients universally coexpressed the lymph node homing molecules CCR7 and L-selectin as well as the differentiation marker CD27, a phenotype consistent with central memory T cells. CCR4 was also universally expressed at high levels, and there was variable expression of other skin addressins (CCR6, CCR10, and CLA). In contrast, T cells isolated from MF skin lesions lacked CCR7/L-selectin and CD27 but strongly expressed CCR4 and CLA, a phenotype suggestive of skin resident effector memory T cells. Our results suggest that SS is a malignancy of central memory T cells and MF is a malignancy of skin resident effector memory T cells.

Adoptive Immunotherapy with Memory T Cells.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. sci-25-sci-25 ◽  
Author(s):  
Helen E. Heslop
Keyword(s):  
T Cells ◽  
T Cell ◽  
Memory T Cells ◽  
Ex Vivo ◽  
Central Memory ◽  
Effector Memory ◽  
Memory Phenotype ◽  
Effector Memory T Cells ◽  
Effector Memory Cells

Clinical adoptive cellular immunotherapy of malignancy and viral infection should transfer T cells that expand in vivo on exposure to antigen and can enter the memory compartment to persist long-term. A number of factors, including cellular phenotype, influence the behavior of the infused line. Primate studies have shown that antigen-specific CD8+ T cell clones only persisted long-term in vivo if they were derived from central memory T cells, but not from effector memory T cells, reacquiring phenotypic and functional properties of memory T cells.1 Other studies have suggested that adoptive transfer of ex vivo-expanded effector memory T cells will have poor survival and clinical efficacy, reporting instead that less differentiated T cells with longer telomeres exhibit longer persistence. These data imply that prolonged ex vivo expansion, required, for example, for T cell cloning, adversely affects subsequent in vivo expansion and survival. However, our trials administering ex vivo-expanded, polyclonal EBV-specific T cell lines demonstrated that expanded effector memory T cells, infused into a lymphodepleted host, can expand massively in vivo, enter the memory compartment, and persist for up to seven years after infusion. Furthermore, in a study infusing trivirus-specific CTLs with effector memory phenotype, we saw expansion of CTLs specific for the latent viruses CMV and EBV. By contrast, adenoviral-specific CTL persisted only in patients who were acutely infected with the agent2 We recently compared non-specifically activated T cells (ATC) with EBV-specific CTLs derived from the same initial peripheral blood collection and expressing distinguishable chimeric GD2-specific chimeric antigen receptors (CARATC and CAR-CTL). In this study, ATCs were cultured for 14 to 21 days. Between 0.9% and 6.1% retained a central memory (CCR7+, CD62L+) phenotype, up to 30% had an effector memory phenotype (CCR7−, CD62L+), and the remainder had a terminally/fully differentiated effector phenotype. By contrast, EBV-CTL were cultured for 30 to 44 days and expressed no CCR7, but up to 50% were CD62L+, and contained cells that were terminally/fully differentiated effectors and effector memory cells. These EBV-CTLs also all had a CD45RO memory phenotype, while about 13% to 60% of ATCs expressed CD45RA, a marker of naïve T cells. Despite these differences in memory subsets, it was the CAR-CTLs that had the clearly greater persistence and could be shown to retain functionality, while CAR-ATC rapidly disappeared from the circulation and could not be recovered. Hence, factors other than phenotype, such as antigenic stimulation and costimulation almost certainly influence cell fate after infusion, and determine whether or not effector memory cells can re-access the central memory pool. Ultimately, strategies that combine selection of optimal phenotype with the provision of antigen stimulation and co-stimulation and a cytokine milieu that favors homeostatic expansion will likely lead to the most effective outcomes following adoptive T cell transfer.

Sign in / Sign up

Export Citation Format

Share Document