scholarly journals CD4 Effector T Cell Subsets in the Response to Influenza

2002 ◽  
Vol 196 (7) ◽  
pp. 957-968 ◽  
Author(s):  
Eulogia Román ◽  
Ellen Miller ◽  
Allen Harmsen ◽  
James Wiley ◽  
Ulrich H. von Andrian ◽  
...  
Keyword(s):  
Interleukin 2 ◽  
Interferon Γ ◽  
T Cell Subsets ◽  
Effector Cells ◽  
Effector T Cell ◽  
Resting Cell ◽  
Cell Divisions ◽  
And Function ◽  
Secondary Lymphoid Organs ◽  
Draining Lymph Nodes

The immune response of naive CD4 T cells to influenza virus is initiated in the draining lymph nodes and spleen, and only after effectors are generated do antigen-specific cells migrate to the lung which is the site of infection. The effector cells generated in secondary organs appear as multiple subsets which are a heterogeneous continuum of cells in terms of number of cell divisions, phenotype and function. The effector cells that migrate to the lung constitute the more differentiated of the total responding population, characterized by many cell divisions, loss of CD62L, down-regulation of CCR7, stable expression of CD44 and CD49d, and transient expression of CCR5 and CD25. These cells also secrete high levels of interferon γ and reduced levels of interleukin 2 relative to those in the secondary lymphoid organs. The response declines rapidly in parallel with viral clearance, but a spectrum of resting cell subsets reflecting the pattern at the peak of response is retained, suggesting that heterogeneous effector populations may give rise to corresponding memory populations. These results reveal a complex response, not an all-or-none one, which results in multiple effector phenotypes and implies that effector cells and the memory cells derived from them can display a broad spectrum of functional potentials.

Recipient immune-competent T lymphocytes can survive intensive conditioning for bone marrow transplantation

Blood ◽  
1986 ◽  
Vol 68 (4) ◽  
pp. 954-956 ◽  
Author(s):  
A Butturini ◽  
RC Seeger ◽  
RP Gale
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
T Lymphocytes ◽  
Graft Rejection ◽  
Marrow Transplantation ◽  
Interleukin 2 ◽  
Marrow Transplant ◽  
Effector Cells ◽  
And Function

Abstract Bone marrow transplantation is usually preceded by intensive chemotherapy and radiation therapy designed to completely eliminate recipient immune-competent cells that might reject the donor bone marrow. We show that seven of 14 bone marrow transplant recipients who received intensive conditioning retained circulating T lymphocytes that proliferate after incubation with interleukin 2 and phytohemagglutinin and function as effector cells in an in vitro model of graft rejection. These T cells may mediate graft rejection.

scholarly journals Regulatory T cell expansion by a highly CD25-dependent IL-2 mutein arrests ongoing autoimmunity

2019 ◽  
Author(s):  
Liliane Khoryati ◽  
Minh Nguyet Pham ◽  
McKenna Sherve ◽  
Swarnima Kumari ◽  
Kevin Cook ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Dose Range ◽  
Interleukin 2 ◽  
Autoimmune Response ◽  
Wild Type ◽  
Effector Cells ◽  
Inflammatory Conditions ◽  
Receptor Component ◽  
And Function

AbstractInterleukin-2 (IL-2) controls the homeostasis and function of regulatory T cells (Tregs) and defects in the IL-2 pathway contribute to multiple autoimmune diseases. Although recombinant IL-2 therapy has been efficacious in certain inflammatory conditions, the capacity for IL-2 to also activate inflammatory effector responses highlights the need for IL-2-based therapeutics with improved Treg-specificity. From a panel of rationally designed IL-2 variants, we identified IL-2 muteins with reduced potency and enhanced Treg-selectivity due to increased dependence on the IL-2-receptor component CD25. As an Fc-fused homodimer, the optimal Fc.IL-2 mutein induced selective Treg enrichment and reduced agonism of effector cells across a wide dose range. Furthermore, despite being a weaker agonist, overall Treg growth was greater and more sustained due to reduced receptor-mediated clearance of the Fc.IL-2 mutein compared to Fc-fused wild-type IL-2. Preferential Treg enrichment was also observed in the presence of activated pathogenic T cells in the autoimmune target organ, despite a loss of Treg-selectivity in an IL-2R-proximal response. These features allowed for extended resolution of spontaneous autoimmunity using infrequent dosing schedules. Thus, IL-2 muteins enable efficient, flexible, and targeted control of the autoimmune response.One Sentence SummaryA CD25-dependent IL-2 mutein selectively expands regulatory T cells and provides potent and targeted control of autoimmunity.

scholarly journals An IL-2 mutein engineered to promote expansion of regulatory T cells arrests ongoing autoimmunity in mice

2020 ◽  
Vol 5 (50) ◽  
pp. eaba5264 ◽  
Author(s):  
Liliane Khoryati ◽  
Minh Nguyet Pham ◽  
McKenna Sherve ◽  
Swarnima Kumari ◽  
Kevin Cook ◽  
...  
Keyword(s):  
T Cells ◽  
Dose Range ◽  
Interleukin 2 ◽  
Nod Mice ◽  
Effector Cells ◽  
Inflammatory Conditions ◽  
Cell Selectivity ◽  
Receptor Component ◽  
Cell Enrichment ◽  
And Function

Interleukin-2 (IL-2) controls the homeostasis and function of regulatory T (Treg) cells, and defects in the IL-2 pathway contribute to multiple autoimmune diseases. Although recombinant IL-2 therapy has been efficacious in certain inflammatory conditions, the capacity for IL-2 to also activate inflammatory effector responses highlights the need for IL-2–based therapeutics with improved Treg cell specificity. From a panel of rationally designed murine IL-2 variants, we identified IL-2 muteins with reduced potency and enhanced Treg cell selectivity due to increased dependence on the IL-2 receptor component CD25. As an Fc-fused homodimer, the optimal Fc.IL-2 mutein induced selective Treg cell enrichment and reduced agonism of effector cells across a wide dose range. Furthermore, despite being a weaker agonist, overall Treg cell growth was greater and more sustained due to reduced receptor-mediated clearance of the Fc.IL-2 mutein compared with Fc-fused wild-type IL-2. Preferential Treg cell enrichment was also observed in the presence of activated pathogenic T cells in the pancreas of nonobese diabetic (NOD) mice, despite a loss of Treg cell selectivity in an IL-2R proximal response. These properties facilitated potent and extended resolution of NOD diabetes with infrequent dosing schedules.

scholarly journals Spontaneous and glucocorticoid-induced apoptosis in human mature T lymphocytes

Blood ◽  
1995 ◽  
Vol 86 (11) ◽  
pp. 4199-4205 ◽  
Author(s):  
M Brunetti ◽  
N Martelli ◽  
A Colasante ◽  
M Piantelli ◽  
P Musiani ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Interleukin 2 ◽  
Cell Number ◽  
T Cell Subsets ◽  
Dependent Manner ◽  
Cell Repertoire ◽  
Induced Apoptosis ◽  
And Function ◽  
Dose Dependent

Glucocorticoid (GC)-induced apoptosis is a well-recognized physiologic regulator of murine T-cell number and function. We have analyzed its mechanisms in human mature T cells, which have been thought to be insensitive until recently. Peripheral blood T cells showed sensitivity to GC-induced apoptosis soon after the proliferative response to a mitogenic stimulation, and were also sensitive to spontaneous (ie, growth factor deprivation-dependent) apoptosis. CD8+ T cells were more sensitive to both forms than CD4+ T cells. Acquisition of sensitivity to GC-induced apoptosis was not associated with any change in number or affinity of GC receptors. Both spontaneous and GC-induced apoptosis were increased by the macromolecular synthesis inhibitors, cycloheximide (CHX) and puromycin. A positive correlation between the degree of protein synthesis inhibition and the extent of apoptosis was observed. Interleukin-2 (IL-2) IL-4, and IL-10 protected (IL-2 > IL-10 > IL-4) T cells from both forms of apoptosis in a dose-dependent manner. Our data suggest that spontaneous and GC-induced apoptosis regulate the human mature T-cell repertoire by acting early after the immune response and differentially affecting T-cell subsets.

scholarly journals Acquisition of Selectin Binding and Peripheral Homing Properties by CD4+ and CD8+ T Cells

1999 ◽  
Vol 189 (11) ◽  
pp. 1765-1776 ◽  
Author(s):  
Huijuan Xie ◽  
Yaw-Chyn Lim ◽  
Francis W. Luscinskas ◽  
Andrew H. Lichtman
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Chemokine Receptors ◽  
Interferon Γ ◽  
T Cell Subsets ◽  
Effector Cells ◽  
Inflammatory Site ◽  
Selectin Ligand ◽  
Inducible Protein ◽  
Selectin Binding

Different T cell subsets exhibit distinct capacities to migrate into peripheral sites of inflammation, and this may in part reflect differential expression of homing receptors and chemokine receptors. Using an adoptive transfer approach, we examined the ability of functionally distinct subsets of T cells to home to a peripheral inflammatory site. The data directly demonstrate the inability of naive T cells and the ability of effector cells to home to inflamed peritoneum. Furthermore, interleukin (IL)-12 directs the differentiation of either CD4+ or CD8+ T cells into effector populations that expresses functional E- and P-selectin ligand and that are preferentially recruited into the inflamed peritoneum compared with T cells differentiated in the presence of IL-4. Recruitment can be blocked by anti–E- and –P-selectin antibodies. The presence of antigen in the peritoneum promotes local proliferation of recruited T cells, and significantly amplifies the Th1 polarization of the lymphocytic infiltrate. Preferential recruitment of Th1 cells into the peritoneum is also seen when cytokine response gene 2 (CRG-2)/interferon γ–inducible protein 10 (IP-10) is used as the sole inflammatory stimulus. We have also found that P-selectin binds only to antigen-specific T cells in draining lymph nodes after immunization, implying that both antigen- and cytokine-mediated signals are required for expression of functional selectin-ligand.

scholarly journals Improved function and balance in T cell modulation by endothelial cells in young people

2021 ◽  
Author(s):  
Shu-Qian Tang ◽  
Wei-Li Yao ◽  
Yazhe Wang ◽  
Yuan-Yuan Zhang ◽  
Hong-Yan Zhao ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Subset ◽  
Underlying Mechanism ◽  
T Cell Subsets ◽  
Effector T Cell ◽  
Improved Function ◽  
And Function

Elderly individuals exhibit unbalanced bone marrow (BM) effector T cell subset differentiation, such as increased T helper (Th)-1 and T cytotoxic (Tc)-1 cell frequencies, but the underlying mechanism still unclear. Endothelial cells (ECs) , which are instructive components of the BM microenvironment, exhibit the phenotype of semi-professional antigen-presenting cells and regulate T cell recruitment and activation. Thus, we compared the frequency and function of BM ECs, especially their capacity to regulate effector T cell subsets, between young and old healthy individuals, and explored the underlying mechanism of this immunomodulatory discrepancy. Although the young and old EC percentages were comparable, young ECs showed less reactive oxygen species and better migratory and tube-forming abilities than old ECs. Notably, young ECs regulated T cells to differentiate into fewer Th1 and Tc1 cells than old ECs. Reduced T cell activation molecules and inflammatory cytokines in young BM ECs may be the possible mechanism.

IL-15 drives neonatal T cells to acquire CD56 and become activated effector cells

Blood ◽  
2003 ◽  
Vol 102 (6) ◽  
pp. 2195-2197 ◽  
Author(s):  
Sharon Cookson ◽  
Denis Reen
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Cord Blood ◽  
Natural Killer ◽  
Interleukin 2 ◽  
Interferon Γ ◽  
Effector Cells ◽  
Cd56 Expression ◽  
Ifn Γ ◽  
Nk Receptor

Abstract Expression of one or more natural killer (NK) receptors on T cells may correlate with effector function. This study investigated the frequency of neonatal NK receptor–positive (NKR+) T cells and their expansionary properties with interleukin-2 (IL-2), IL-7, or IL-15. While cord blood contains significantly decreased frequencies of NKR+ T cells compared with adult blood, newborn CD56+CD3+ cells could be expanded 200-fold during culture with IL-15. By depleting CD56+ cells, we were able to determine that this expansion was due to a subpopulation of T cells acquiring CD56 expression. Moreover, CD56 acquisition was associated with a distinct CD8+CD25+ interferon γ–positive (IFN-γ+) phenotype. This property could therefore be exploited during bone marrow reconstitution and may partially account for the resilience of the newborn to infection.

scholarly journals IL-12 signaling drives the differentiation and function of a TH1-derived TFH1-like cell population

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Michael D. Powell ◽  
Kaitlin A. Read ◽  
Bharath K. Sreekumar ◽  
Devin M. Jones ◽  
Kenneth J. Oestreich
Keyword(s):  
Immune Responses ◽  
Cell Population ◽  
Cell Activation ◽  
Cell Formation ◽  
Interferon Γ ◽  
T Cell Subsets ◽  
B Cell Activation ◽  
T Helper 1 ◽  
Follicular Helper ◽  
And Function

Abstract CD4+ T follicular helper (TFH) cells provide help to B cells and promote antibody-mediated immune responses. Increasing evidence supports the existence of TFH populations that secrete cytokines typically associated with the effector functions of other CD4+ T cell subsets. These include T helper 1 (TH1)-biased TFH (TFH1) cells that have recognized roles in both immune responses to pathogens and also the pathogenesis of autoimmune disease. Given their apparent importance to human health, there is interest in understanding the mechanisms that regulate TFH1 cell formation and function. However, their origin and the molecular requirements for their differentiation are unclear. Here, we describe a population of murine TH1-derived, TFH1-like cells that express the chemokine receptor Cxcr3 and produce both the TH1 cytokine interferon-γ and the TFH-associated cytokine interleukin-21 (IL-21). Furthermore, these TFH1-like cells promote B cell activation and antibody production at levels indistinguishable from conventional IL-6-derived TFH-like cells. Regarding their regulatory requirements, we find that IL-12 signaling is necessary for the differentiation and function of this TFH1-like cell population. Specifically, IL-12-dependent activation of STAT4, and unexpectedly STAT3, promotes increased expression of IL-21 and the TFH lineage-defining transcription factor Bcl-6 in TFH1-like cells. Taken together, these findings provide insight into the potential origin and differentiation requirements of TFH1 cells.

Lymphoproliferative defects in mice lacking the expression of neurofibromin: functional and biochemical consequences ofNf1 deficiency in T-cell development and function

Blood ◽  
2002 ◽  
Vol 100 (10) ◽  
pp. 3656-3662 ◽  
Author(s):  
David A. Ingram ◽  
Lei Zhang ◽  
Jennifer McCarthy ◽  
Mary Jo Wenning ◽  
Lucy Fisher ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Absolute Number ◽  
Suppressor Gene ◽  
T Cell Subsets ◽  
Lymphocyte Development ◽  
And Function

Ras plays an essential role in lymphocyte development and function. However, in vivo consequence(s) of regulation of Ras activity by guanosine triphosphatase (GTPase)–activating proteins (GAPs) on lymphocyte development and function are not known. In this study we demonstrate that neurofibromin, the protein encoded by theNF1 tumor suppressor gene functions as a GAP for Ras in T cells. Loss of Nf1 in T cells results in enhanced Ras activation, which is associated with thymic and splenic hyperplasia, and an increase in the absolute number of immature and mature T-cell subsets compared with control mice. Interestingly, in spite of a profound T-cell expansion and higher thymidine incorporation in unstimulated Nf1-deficient T cells, T-cell receptor and interleukin-2 receptor–mediated proliferation of thymocytes and mature T cells was substantially reduced compared with control mice. Collectively, these results identify neurofibromin as a GAP for Ras in T cells for maintaining immune homeostasis in vivo.

Graft-versus-host-reactive donor CD4 cells can induce T cell-mediated rejection of the donor marrow in mixed allogeneic chimeras prepared with nonmyeloablative conditioning

Blood ◽  
2004 ◽  
Vol 103 (2) ◽  
pp. 732-739 ◽  
Author(s):  
Yong-Mi Kim ◽  
Markus Y. Mapara ◽  
Julian D. Down ◽  
Kevin W. Johnson ◽  
Florence Boisgerault ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Interleukin 2 ◽  
Early Time ◽  
Interferon Γ ◽  
T Cell Subsets ◽  
Cd8 Cells ◽  
Graft Versus Host ◽  
Donor Chimerism ◽  
Αβ T Cells

Abstract Murine mixed hematopoietic chimerism can be achieved following nonmyeloablative conditioning with cyclophosphamide, T cell–depleting monoclonal antibodies, and thymic irradiation. Donor lymphocyte infusions (DLIs) 35 days after bone marrow transplantation (BMT) convert mixed to full donor chimerism and mediate graft-versus-lymphoma effects without graft-versus-host disease. We evaluated the role of T-cell subsets in DLIs in converting mixed to full donor chimerism in a fully major histocompatibility complex–mismatched strain combination. Whereas DLIs administered on day 35 converted 100% of mixed chimeras to full donor chimerism, conversion was less frequent when either CD4 or CD8 cells were depleted, indicating that both subsets contribute to the conversion. Surprisingly, administration of CD8-depleted DLIs led to complete loss of donor chimerism in a high proportion (54%) of recipients compared with CD4-plus CD8-depleted DLIs (15%) or CD4-depleted DLIs (0%) (P < .05). DLIs administered at early time points after BMT (eg, day 21) also precipitated rejection of donor marrow by recipient αβ T cells, in association with donor CD4 cell expansion and high production of interleukin 2 (IL-2), IL-4, and interferon-γ. Thus, DLIs can paradoxically induce marrow rejection by residual host αβ T cells. These results have implications for the timing of and use of subset depletion of DLIs in recipients of nonmyeloablative transplants.

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