scholarly journals Combined TLR and CD40 Triggering Induces Potent CD8+ T Cell Expansion with Variable Dependence on Type I IFN

2004 ◽  
Vol 199 (6) ◽  
pp. 775-784 ◽  
Author(s):  
Cory L. Ahonen ◽  
Christie L. Doxsee ◽  
Sean M. McGurran ◽  
Tony R. Riter ◽  
William F. Wade ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Expansion ◽  
Cd8 T Cell ◽  
Secondary Response ◽  
Type I ◽  
Type I Ifn ◽  
Vaccine Adjuvants ◽  
Cell Responses ◽  
T Cell Expansion

Toll-like receptors are important in the activation of innate immunity, and CD40 is a molecule critical for many T and B cell responses. Whereas agonists for either pathway have been used as vaccine adjuvants, we show that a combination of Toll-like receptor (TLR)7 and CD40 agonists synergize to stimulate CD8+ T cell responses 10–20-fold greater than the use of either agonist alone. Antigen-specific CD8+ T cells elicited from combination CD40/TLR7 treatment demonstrated both lytic activities and interferon (IFN)γ production and an enhanced secondary response to antigenic challenge. Agonists for TLRs 2/6, 3, 4, and 9 also synergized with CD40 stimulation, demonstrating that synergy with the CD40 pathway is a property of TLR-derived stimuli in general. The CD8+ T cell expansion induced by CD40/TLR7 triggering was independent of CD4+ T cells, IFNγ, and IL-12 but dependent on B7-mediated costimulation and surprisingly on type I IFN. These studies provide the rational basis for the use of TLR and CD40 agonists together as essential adjuvants to optimize vaccines designed to elicit protective or therapeutic immunity.

scholarly journals B cell depletion impairs vaccination-induced CD8+ T cell responses in a type I interferon-dependent manner

2021 ◽  
pp. annrheumdis-2021-220435
Author(s):  
Theresa Graalmann ◽  
Katharina Borst ◽  
Himanshu Manchanda ◽  
Lea Vaas ◽  
Matthias Bruhn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Expansion ◽  
De Novo ◽  
T Cell Responses ◽  
Type I ◽  
Cell Responses ◽  
T Cell Expansion

ObjectivesThe monoclonal anti-CD20 antibody rituximab is frequently applied in the treatment of lymphoma as well as autoimmune diseases and confers efficient depletion of recirculating B cells. Correspondingly, B cell-depleted patients barely mount de novo antibody responses during infections or vaccinations. Therefore, efficient immune responses of B cell-depleted patients largely depend on protective T cell responses.MethodsCD8+ T cell expansion was studied in rituximab-treated rheumatoid arthritis (RA) patients and B cell-deficient mice on vaccination/infection with different vaccines/pathogens.ResultsRituximab-treated RA patients vaccinated with Influvac showed reduced expansion of influenza-specific CD8+ T cells when compared with healthy controls. Moreover, B cell-deficient JHT mice infected with mouse-adapted Influenza or modified vaccinia virus Ankara showed less vigorous expansion of virus-specific CD8+ T cells than wild type mice. Of note, JHT mice do not have an intrinsic impairment of CD8+ T cell expansion, since infection with vaccinia virus induced similar T cell expansion in JHT and wild type mice. Direct type I interferon receptor signalling of B cells was necessary to induce several chemokines in B cells and to support T cell help by enhancing the expression of MHC-I.ConclusionsDepending on the stimulus, B cells can modulate CD8+ T cell responses. Thus, B cell depletion causes a deficiency of de novo antibody responses and affects the efficacy of cellular response including cytotoxic T cells. The choice of the appropriate vaccine to vaccinate B cell-depleted patients has to be re-evaluated in order to efficiently induce protective CD8+ T cell responses.

Concomitant type I IFN receptor-triggering of T cells and of DC is required to promote maximal modified vaccinia virus Ankara-induced T-cell expansion

2010 ◽  
Vol 40 (10) ◽  
pp. 2769-2777 ◽  
Author(s):  
Theresa Frenz ◽  
Zoe Waibler ◽  
Janin Hofmann ◽  
Matthias Hamdorf ◽  
Markus Lantermann ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Vaccinia Virus ◽  
Cell Expansion ◽  
Type I ◽  
Type I Ifn ◽  
Modified Vaccinia Virus Ankara ◽  
T Cell Expansion

scholarly journals The viral context instructs the redundancy of costimulatory pathways in driving CD8+ T cell expansion

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Suzanne PM Welten ◽  
Anke Redeker ◽  
Kees LMC Franken ◽  
Jennifer D Oduro ◽  
Ferry Ossendorp ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Expansion ◽  
Costimulatory Molecule ◽  
Cd8 T Cell ◽  
Lymphocytic Choriomeningitis ◽  
Type I ◽  
Costimulatory Signals ◽  
T Cell Expansion

Signals delivered by costimulatory molecules are implicated in driving T cell expansion. The requirements for these signals, however, vary from dispensable to essential in different infections. We examined the underlying mechanisms of this differential T cell costimulation dependence and found that the viral context determined the dependence on CD28/B7-mediated costimulation for expansion of naive and memory CD8+ T cells, indicating that the requirement for costimulatory signals is not imprinted. Notably, related to the high-level costimulatory molecule expression induced by lymphocytic choriomeningitis virus (LCMV), CD28/B7-mediated costimulation was dispensable for accumulation of LCMV-specific CD8+ T cells because of redundancy with the costimulatory pathways induced by TNF receptor family members (i.e., CD27, OX40, and 4-1BB). Type I IFN signaling in viral-specific CD8+ T cells is slightly redundant with costimulatory signals. These results highlight that pathogen-specific conditions differentially and uniquely dictate the utilization of costimulatory pathways allowing shaping of effector and memory antigen-specific CD8+ T cell responses.

Uraemia-induced immune senescence and clinical outcomes in chronic kidney disease patients

2018 ◽  
Vol 35 (4) ◽  
pp. 624-632 ◽  
Author(s):  
Thomas Crépin ◽  
Mathieu Legendre ◽  
Clémence Carron ◽  
Clément Vachey ◽  
Cécile Courivaud ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
T Cells ◽  
T Cell ◽  
Kidney Disease ◽  
Cell Expansion ◽  
Cd8 T Cell ◽  
Immune Senescence ◽  
Thymic Output ◽  
Age Related ◽  
T Cell Expansion

Abstract Background Patients with chronic kidney disease (CKD) are more prone to develop premature age-related diseases. Data on immune senescence are scarce in CKD populations, except in end-stage renal disease and dialysis. We designed a longitudinal prospective study to evaluate immune senescence at different CKD stages and its influence on CKD patient outcomes. Methods Clinical and biological data collections were performed on 222 patients at different CKD stages [1–2 (n = 85), 4 (n = 53) and 5 (n = 84)]. Immune senescence biomarkers were measured by cytometry on T cells (CD28, CD57, CD45RA, CD31, γH2A.X) or by quantitative polymerase chain reaction [relative telomere length (RTL)] on peripheral blood mononuclear cells and analysed according to CKD stages and outcomes. Results CKD was associated with an increase in immune senescence and inflammation biomarkers, as follows: low thymic output (197 ± 25 versus 88 ± 13 versus 73 ± 21 CD4+CD45RA+CD31+ T cells/mm3), an increased proportion of terminally differentiated T cells (CD8+CD28−CD57+) (24 ± 18 versus 32 ± 17 versus 35 ± 19%) restricted to cytomegalovirus-positive patients, telomere shortening (1.11 ± 0.36 versus 0.78 ± 0.24 versus 0.97 ± 0.21 telomere:single copy ratio) and an increase in C-reactive protein levels [median 2.9 (range 1.8–4.9) versus 5.1 (27–9.6) versus 6.2 (3.4–10.5) mg/L]. In multivariate analysis, shorter RTL was associated with death {hazard ratio [HR] 4.12 [95% confidence interval (CI) 1.44–11.75]}. Low thymic output was associated with infections [HR 1.79 (95% CI (1.34–9.58)] and terminally differentiated CD8+ T-cell expansion with a risk of cardiovascular events [CEs; HR 4.86 (95% CI 1.72–13.72)]. Conclusion CKD was associated with premature immune ageing. Each of these alterations increased the risk of specific age-related diseases, such as RTL and death, thymic function and infections and terminally differentiated CD8+ T-cell expansion and CEs.

scholarly journals Interrupting CD28 costimulation before antigen rechallenge affects CD8+T-cell expansion and effector functions during secondary response in mice

2016 ◽  
Vol 46 (7) ◽  
pp. 1644-1655 ◽  
Author(s):  
Monika Fröhlich ◽  
Tea Gogishvili ◽  
Daniela Langenhorst ◽  
Fred Lühder ◽  
Thomas Hünig
Keyword(s):  
T Cell ◽  
Cell Expansion ◽  
Cd8 T Cell ◽  
Secondary Response ◽  
Effector Functions ◽  
Cd28 Costimulation ◽  
T Cell Expansion

T Cell Responses during Long-Term Continuous Infusion of MT103 (MEDI-538; Anti-CD19 BiTE) in Patients with Relapsed B-NHL: Data from Dose-Escalation Study MT103-104.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2725-2725 ◽  
Author(s):  
Matthias Klinger ◽  
Peter Kufer ◽  
Petra Kirchinger ◽  
Ralf Lutterbüse ◽  
Eugen Leo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Dose Escalation ◽  
Cell Expansion ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
Cell Counts ◽  
T Cell Expansion

Abstract MT103 (MEDI-538) is a bispecific single-chain antibody construct directed at CD3 on human T cells and CD19 on human B lymphoma and normal B cells. Transient linkage of B and T cells by MT103 provides T cells with a T cell receptor (TCR)-like signal leading to redirected lysis of B cell targets without apparent need of costimulation and inducing T cells to proliferate, secrete cytokines and upregulate surface activation markers. TCR-like signalling by MT103 is strictly dependent on the presence of target cells. Redirected lysis of CD19-positive cells by MT103 is seen at low picomolar concentrations and at low effector-to-target ratios. The in-vivo half-life of MT103 is approximately two hours. In the ongoing dose escalation study MT103-104, patients with relapsed B-NHL have so far received continuous infusion of MT103 at maintenance flow-rates of 0.5, 1.5, 5 and 15 μg/m2/24h for 4 or 8 weeks following a 3+3 dose escalation design. Serum concentrations of MT103 remained constant over the entire treatment period at a level depending on the respective maintenance flow-rate. Depletion of circulating B (lymphoma) cells could be observed more frequently with increasing dose levels (DL) from DL1 to DL3, and in all evaluable patients at DL4. Three of six evaluable patients at DL4 showed clinical responses (2 PR, 1 CR) according to standardized Cheson criteria, but no patient of DL1-3. The time courses of absolute CD4 and CD8 T cell counts in peripheral blood were determined by flow cytometry. CD8 T lymphocytes were further subdivided for analysis into naïve T cells, TCM (central memory T cells), TEM (effector memory T cells) and TEMRA (non-proliferating terminally differentiated CTL), and CD4 T lymphocytes into naïve T cells, TCM and TEM. Activation of CD4 and CD8 T cell subsets was determined by measuring upregulation of CD69, CD25 and HLA-DR. Serum levels of cytokines were determined as additional biomarkers for T cell activation. In 50% of patients at DL1 to DL3, CD4 and CD8 T cell counts increased during the course of treatment - over pre-treatment levels. The TEM subset from both CD4 and CD8 T cells accounted for most of the observed increases, while the naïve T cell subsets showed no increase but also no signs of apoptosis. The non-proliferative TEMRA subset of CD8 T cells also remained unchanged in most patients. This indicated that the selective increase of proliferation-competent TEM subsets was attributed to MT103-induced T cell proliferation. At DL4, all evaluable patients showed signs of T cell expansion after 2 weeks of MT103 infusion, which was most pronounced in those who developed a partial or complete remission. The increase of CD8 T cell counts was more pronounced than that of CD4 T cells. T cell expansion was accompanied by upregulation of T cell activation markers as well as by increases in serum concentrations of cytokines like IFN-γ. T cell expansion and activation reverted in all cases when the infusion of MT103 was stopped. In summary, MT103 induced a reversible secondary T cell response involving T cell activation and proliferation as well as T cell cytotoxicity against circulating B cells and lymphoma tissue. The dose-dependent T cell expansion observed during long-term infusion of MT103, particularly within the cytotoxic TEM subset of CD8 T cells, appears to play a key role for clinical activity.

Tissue Parenchymal Cell Expression of B7-H1 Inhibits Infiltrating T Cell Expansion and Prevents Persistence of Graft-Versus-Host Disease

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2974-2974
Author(s):  
Xiaofan Li ◽  
Wei He ◽  
Ruishu Deng ◽  
Can Liu ◽  
Miao Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Expansion ◽  
Cd8 T Cell ◽  
Target Tissue ◽  
T Cell Expansion ◽  
Parenchymal Cells

Abstract Abstract 2974 Alloreactive donor CD8+ T cells facilitate engraftment and mediate graft versus leukemia (GVL) effects but also cause graft versus host disease (GVHD) in murine and human recipients after allogeneic hematopoietic cell transplantation (HCT). B7-H1 (PD-L1) expression by antigen-presenting cells has an important role in tolerizing activated T cells by binding to PD-1. We and others previously reported that disruption of binding between B7-H1 and PD-1 augments acute GVHD. Parenchymal cells do not usually express B7-H1 but can be induced by inflammatory cytokines (i.e. IFN-g) to express B7-H1. The role of B7-H1 expression by parenchymal tissue cells in regulating the expansion and persistence of donor CD8+ cells in tissues of mice with GVHD has not yet been evaluated. In the current studies, we evaluated the role of B7-H1 expression by GVHD target tissues in regulating donor CD8+ T cell function in 3 different experimental GVHD systems, using in vivo bioluminescent imaging (BLI), in vivo BrdU-labeling, and in vitro proliferation assays. The first system evaluated the role of B7-H1 expression in TBI-conditioned recipients. In these recipients, injected donor CD8+ T cells showed two waves of expansion that correlated with two phases of clinical GVHD. The first wave of donor CD8+ T cell expansion was associated with upregulated expression of B7-H1 in GVHD target tissues and only weak clinical GVHD. The second wave of donor CD8+ T cell expansion was associated with loss of B7-H1 expression, vigorous donor CD8+ T proliferation and expansion in the GVHD target tissues, and lethal GVHD. In a gain-of-function experiment, B7-H1 expression was induced in hepatocytes by hydrodynamic injection of B7-H1 cDNA during the second wave of T cell expansion in mice with GVHD; this subsequently decreased T cell expansion in the liver and ameliorated GVHD. The second system evaluated the role of B7-H1 expression in anti-CD3-conditioned recipients. In wild-type recipients, injected donor CD8+ T cells had only a single wave of expansion, and the mice had no signs of GVHD. B7-H1 expression by tissue cells (i.e. hepatocytes) was up-regulated, and the tissue infiltrating donor CD8+ T cells were anergic. In B7-H1−/− recipients, injected donor CD8+ T cells proliferated vigorously in GVHD target tissues and caused lethal GVHD.The third system evaluated the role of B7-H1 in unconditioned Rag-2−/− recipients after administration of blocking anti-B7-H1 and in the B7-H1−/−Rag-2−/− chimeras with B7-H1 sufficient Rag-2−/− bone marrow cells, in which B7-H1 deficiency was only in tissue parenchymal cells. Both blockade of B7-H1 and B7-H1 deficiency in parenchymal cells resulted in vigorous donor CD8+ T proliferation in GVHD target tissues and caused lethal GVHD. Taken together, these results show that expression of B7-H1 in GVHD target tissue parenchymal cells plays an important role in regulating the proliferation of infiltrating donor CD8+ T cells and preventing the persistence of GVHD. Our studies also indicate that TBI but not anti-CD3 conditioning can lead to loss of GVHD target tissue cell expression of B7-H1 and persistence of GVHD. Disclosures: No relevant conflicts of interest to declare.

Immunogenetic Characterization of Primary Immune Thrombocytopenia (ITP) in Adults: Preliminary Results of the Unit Study.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2192-2192
Author(s):  
Francesco Zaia ◽  
Elena Boggio ◽  
Davide Rossi ◽  
Eleonora Toffoletti ◽  
Giuseppe Cappellano ◽  
...  
Keyword(s):  
T Cells ◽  
Amino Acid ◽  
T Cell ◽  
Amino Acid Substitution ◽  
Cell Expansion ◽  
Clinical Presentation ◽  
Function Analysis ◽  
Similar Distribution ◽  
Type I ◽  
T Cell Expansion

Abstract Abstract 2192 Background. In adults, ITP displays variable clinical presentation and different response to steroid, Rituximab, and other immune suppressive agents. The pathophysiological differences underlying these different behaviours are mostly unknown and a better knowledge of this biological heterogeneity might help identifying more targeted and rationale treatments for this disease. Purpose. To identify immunogenetic features distinguishing ITP patients from control and different subsets of ITP patients based on clinical presentation and responsiveness to steroid or Rituximab. Several biological analyses were based on the model of autoimmune lymphoprolipherative syndrome (ALPS), a pediatric disease due to genetic defects decreasing function of the Fas death receptor involved in shutting off the immune response and cytotoxic cell function. ALPS displays polyclonal lymphoproliferation, peripheral blood (PB) expansion of TCRαβ+ T-cells double negative for CD4 and CD8 (DN T-cells) and autoimmune manifestations frequently including thrombocytopenia. ALPS is mostly due to deleterious mutations of the Fas gene, but the +1239A>C single nucleotide polymorphism (SNP) of the osteopontin gene (OPN) and several variations of the perforin gene (PRF1) can act as disease modifier. Moreover, defective Fas function and these OPN and PRF1 variations are also displayed by subsets of patients with multiple sclerosis, type-I diabetes mellitus, systemic lupus erythematosus, progressive sclerosis, and chronic inflammatory demyelinating polyneuropathy. Patients and Methods. Adult patients with ITP and matched controls were selected for the analyses and stratified in different clinical subsets according to the disease severity and responsiveness to therapy (asymptomatic, steroid or Rituximab sensitive vs. steroid or Rituximab refractory). Analyses included evaluation of Fas-mediated apoptosis in T cell cultures; proportions of DN-T cells in PB; typing of the +1239A>C SNP of OPN and sequencing of PRF1. All patients were also investigated for TCR monoclonality, whereas BCR monoclonality was analysed in Rituximab-untreated patients only. Results. Analysis of Fas function and DN T-cell expansion was assessed in 100 ITP patients and showed that they displayed higher frequency of defective Fas function than the controls (17/100 vs. 5/100; P<0.05). Expansion of DN T-cells was detected in 2/17 (12%) patients displaying defective Fas function and 3/83 (4%) of those with normal Fas function. Analysis of PRF1 and OPN was performed in 64 patients. Sequencing of PRF1 detected three patients carrying two rare variations; two carried the N252S amino acid substitution (previously described in ALPS) and one the novel R385W amino acid substitution. The overall frequency of these rare variations was higher in the patients than in the controls (4.7% vs. 0.8%, P<0.05). By contrast, the OPN +1239A>C SNP displayed a similar distribution in the patients and the controls. TCR monoclonality was assessed in 76 patients and was detected in 4 of them (5%). BCR monoclonality was assessed in 17 patients in PB and bone marrow and it was always absent. No statistical differences of these parameters were detected comparing patients refractory vs. sensitive to either Rituximab or steroid treatments. However, a trend was found for DN T-cell expansion that tended to be more frequent in Rituximab resistant vs. sensitive patients (0/13 vs. 4/20, P=0.13). Conclusions. These preliminary analyses detected some differences between ITP patients and controls suggesting that defects involved in ALPS development may play a role in adult ITP too. Increasing the patient number is needed to confirm these data and, possibly, to detect differences between clinical subgroups. Disclosures: Off Label Use: Rituximab in ITP.

Perforin Is Important For Both CD4+ and CD8+ T Cell-Mediated Graft-Versus-Tumor Effect But Plays Differential Roles In CD4+ and CD8+ T Cell Expansion After Allogeneic Transplantation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3255-3255
Author(s):  
Nicholas Leigh ◽  
Guanglin Bian ◽  
Wei Du ◽  
George L. Chen ◽  
Hong Liu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Cell Expansion ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
T Cell Proliferation ◽  
T Cell Expansion ◽  
Time Point

Abstract Graft versus tumor (GVT) effect is the desired and integral outcome for successful allogeneic bone marrow transplantation (allo-BMT) for cancer patients. This effect is dependent on T cell mediated recognition and elimination of residual host tumor cells present after allo-BMT. T cell killing is mediated primarily via three pathways: perforin/granzymes, Fas/FasL, and cytotoxic cytokines. Recent work from our lab has revealed a detrimental role for granzyme B (GzmB) in GVT effect due to its role in activation induced cell death (AICD) of CD8+ T cells. As a result, GzmB-/- CD8+ T cells exhibited higher expansion after allo-BMT and subsequently provided better tumor control. Our current study sought to determine the role of perforin (Prf1) in GVT effect mediated by both CD4+ and CD8+ T cells. Using the MHC-mismatched C57BL/6 (H-2b) to BALB/c (H-2d) allo-BMT model, we first confirmed previous findings that when transplanting CD8+ T cells along with T cell depleted (TCD) BM cells, donor CD8+ T cells require Prf1 to mediate GVT effect against allogeneic A20 lymphoma (Fig 1A, Prf1-/- (n=4) vs WT (n=4), *P<0.05). In addition, our data suggest that Prf1 is also required for CD4+ T cells to effectively mediate GVT effect against A20, as transplant with Prf1-/- CD4+CD25- T cells does not control tumor growth as well as WT controls (Fig 1B). Our previous work showed that GzmB deficiency allows for less AICD and subsequently more CD8+ T cell expansion. New data now show a similar effect for Prf1 in CD8+ T cell accumulation, as Prf1-/- CD8+ T cells outcompete WT CD8+ T cells (CD45.1+) when these two genotypes are mixed in equal numbers and transplanted into tumor bearing BALB/c mice (n=5/time point, *P=0.02 day 9)(Fig 1C). This competitive advantage was due to less AICD in the Prf1-/- CD8+ T cells. However, Prf1 appears to be required for efficient GVT activity, because the higher number of Prf1-/- CD8+ T cells are still less capable than WT counterparts in controlling tumor growth. We next tested the effect of Prf1 in AICD in CD4+CD25- T cells, and again co-transplanted WT CD45.1+ and Prf1-/- CD4+CD25- T cells into tumor bearing mice for a competition assay. Unexpectedly, WT CD4+CD25- T cells accumulate to significantly higher numbers when in direct competition with Prf1-/- CD4+CD25- T cells (n=4/time point, **,P<0.01)(Fig 1D). When we measured apoptotic cells with Annexin V staining, we found that WT CD4+CD25- T cells still had significantly more AICD (Prf1-/- 38.3 ± 4.2% vs. WT 48.1 ± 5.1%, P<0.01 on day 7 post-BMT; Prf1-/- 12.7 ± 1.0% vs. WT 18.1 ± 3.4%, P<0.03 on day 9 post-BMT). This result suggests that while Prf1 has an important role in AICD, it may also play a role in another feature of CD4+ T cell biology. We then explored the hypothesis that may Prf1 promote CD4+ T cell proliferation by evaluating Hoescht staining on day 9 post-BMT. Preliminary results suggest that Prf1 may enhance T cell proliferation, as Prf1-/- CD4+ T cells have less actively dividing cells at this time point. Therefore, Prf1 appears to have a surprising role after allo-BMT in sustaining T cell expansion for CD4+ T cells, but not for CD8+ T cells. Another factor influencing GVT effect may be T cell phenotype. Our previous work with CD8+ T cells suggests that more effector memory (CD62LLOWCD44HIGH) T cells accumulate in the absence of GzmB, and that GzmB-/- CD8+ T cells exhibited higher GVT activity than WT controls. We now found that while Prf1-/- CD4+ T cells also skewed towards the effector memory phenotype (CD62LLOWCD44HIGH), loss of Prf1 still reduced the ability of CD4+ T cells to control tumor growth in this model of allo-BMT. In summary, our results suggest that Prf1 plays an important role in GVT responses mediated not only by CD8+ T cells but also by CD4+ T cells, which were shown in previous literature to mainly utilize Fas ligand and cytokine systems to mediate GVT activity. In addition, Prf1 can cause AICD to both CD4+ and CD8+ T cells after allo-BMT. While Prf1-induced AICD reduces CD8+ T cell expansion, Prf1 appears to play a previously unrecognized role enhancing CD4+ T cell proliferation via an unidentified mechanism. Disclosures: No relevant conflicts of interest to declare.

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