scholarly journals T-cell agonists in cancer immunotherapy

2020 ◽  
Vol 8 (2) ◽  
pp. e000966
Author(s):  
Yeonjoo Choi ◽  
Yaoyao Shi ◽  
Cara L Haymaker ◽  
Aung Naing ◽  
Gennaro Ciliberto ◽  
...  
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Current Knowledge ◽  
Checkpoint Inhibitors ◽  
Costimulatory Molecules ◽  
The Body

Cancer cells can evade immune surveillance in the body. However, immune checkpoint inhibitors can interrupt this evasion and enhance the antitumor activity of T cells. Other mechanisms for promoting antitumor T-cell function are the targeting of costimulatory molecules expressed on the surface of T cells, such as 4-1BB, OX40, inducible T-cell costimulator and glucocorticoid-induced tumor necrosis factor receptor. In addition, CD40 targets the modulation of the activation of antigen-presenting cells, which ultimately leads to T-cell activation. Agonists of these costimulatory molecules have demonstrated promising results in preclinical and early-phase trials and are now being tested in ongoing clinical trials. In addition, researchers are conducting trials of combinations of such immune modulators with checkpoint blockade, radiotherapy and cytotoxic chemotherapeutic drugs in patients with advanced tumors. This review gives a comprehensive picture of the current knowledge of T-cell agonists based on their use in recent and ongoing clinical trials.

scholarly journals TRPM2 Is Not Required for T-Cell Activation and Differentiation

2022 ◽  
Vol 12 ◽  
Author(s):  
Niels C. Lory ◽  
Mikolaj Nawrocki ◽  
Martina Corazza ◽  
Joanna Schmid ◽  
Valéa Schumacher ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Transient Receptor Potential ◽  
Cell Function ◽  
Intestinal Inflammation ◽  
Activation Markers

Antigen recognition by the T-cell receptor induces a cytosolic Ca2+ signal that is crucial for T-cell function. The Ca2+ channel TRPM2 (transient receptor potential cation channel subfamily M member 2) has been shown to facilitate influx of extracellular Ca2+ through the plasma membrane of T cells. Therefore, it was suggested that TRPM2 is involved in T-cell activation and differentiation. However, these results are largely derived from in vitro studies using T-cell lines and non-physiologic means of TRPM2 activation. Thus, the relevance of TRPM2-mediated Ca2+ signaling in T cells remains unclear. Here, we use TRPM2-deficient mice to investigate the function of TRPM2 in T-cell activation and differentiation. In response to TCR stimulation in vitro, Trpm2-/- and WT CD4+ and CD8+ T cells similarly upregulated the early activation markers NUR77, IRF4, and CD69. We also observed regular proliferation of Trpm2-/- CD8+ T cells and unimpaired differentiation of CD4+ T cells into Th1, Th17, and Treg cells under specific polarizing conditions. In vivo, Trpm2-/- and WT CD8+ T cells showed equal specific responses to Listeria monocytogenes after infection of WT and Trpm2-/- mice and after transfer of WT and Trpm2-/- CD8+ T cells into infected recipients. CD4+ T-cell responses were investigated in the model of anti-CD3 mAb-induced intestinal inflammation, which allows analysis of Th1, Th17, Treg, and Tr1-cell differentiation. Here again, we detected similar responses of WT and Trpm2-/- CD4+ T cells. In conclusion, our results argue against a major function of TRPM2 in T-cell activation and differentiation.

scholarly journals Hypoxia-induced PD-L1/PD-1 crosstalk impairs T-cell function in sleep apnoea

2017 ◽  
Vol 50 (4) ◽  
pp. 1700833 ◽  
Author(s):  
Carolina Cubillos-Zapata ◽  
Jose Avendaño-Ortiz ◽  
Enrique Hernandez-Jimenez ◽  
Victor Toledano ◽  
Jose Casas-Martin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Intermittent Hypoxia ◽  
Cell Activation ◽  
Cell Function ◽  
Sleep Apnoea ◽  
Orphan Receptor ◽  
Dependent Manner ◽  
Obstructive Sleep

Obstructive sleep apnoea (OSA) is associated with higher cancer incidence, tumour aggressiveness and cancer mortality, as well as greater severity of infections, which have been attributed to an immune deregulation. We studied the expression of programmed cell death (PD)-1 receptor and its ligand (PD-L1) on immune cells from patients with OSA, and its consequences on immune-suppressing activity. We report that PD-L1 was overexpressed on monocytes and PD-1 was overexpressed on CD8+ T-cells in a severity-dependent manner. PD-L1 and PD-1 overexpression were induced in both the human in vitro and murine models of intermittent hypoxia, as well as by hypoxia-inducible factor-1α transfection. PD-L1/PD-1 crosstalk suppressed T-cell proliferation and activation of autologous T-lymphocytes and impaired the cytotoxic activity of CD8+ T-cells. In addition, monocytes from patients with OSA exhibited high levels of retinoic acid related orphan receptor, which might explain the differentiation of myeloid-derived suppressor cells. Intermittent hypoxia upregulated the PD-L1/PD-1 crosstalk in patients with OSA, resulting in a reduction in CD8+ T-cell activation and cytotoxicity, providing biological plausibility to the increased incidence and aggressiveness of cancer and the higher risk of infections described in these patients.

scholarly journals Transient and persistent effects of IL-15 on lymphocyte homeostasis in nonhuman primates

Blood ◽  
2010 ◽  
Vol 116 (17) ◽  
pp. 3238-3248 ◽  
Author(s):  
Enrico Lugli ◽  
Carolyn K. Goldman ◽  
Liyanage P. Perera ◽  
Jeremy Smedley ◽  
Rhonda Pung ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
The Body ◽  
Effector Memory ◽  
Memory Cd8 T Cells

Abstract Interleukin-15 (IL-15) is a cytokine with potential therapeutic application in individuals with cancer or immunodeficiency to promote natural killer (NK)– and T-cell activation and proliferation or in vaccination protocols to generate long-lived memory T cells. Here we report that 10-50 μg/kg IL-15 administered intravenously daily for 12 days to rhesus macaques has both short- and long-lasting effects on T-cell homeostasis. Peripheral blood lymphopenia preceded a dramatic expansion of NK cells and memory CD8 T cells in the circulation, particularly a 4-fold expansion of central memory CD8 T cells and a 6-fold expansion of effector memory CD8 T cells. This expansion is a consequence of their activation in multiple tissues. A concomitant inverted CD4/CD8 T-cell ratio was observed throughout the body at day 13, a result of preferential CD8 expansion. Expanded T- and NK-cell populations declined in the blood soon after IL-15 was stopped, suggesting migration to extralymphoid sites. By day 48, homeostasis appears restored throughout the body, with the exception of the maintenance of an inverted CD4/CD8 ratio in lymph nodes. Thus, IL-15 generates a dramatic expansion of short-lived memory CD8 T cells and NK cells in immunocompetent macaques and has long-term effects on the balance of CD4+ and CD8+ T cells.

scholarly journals Modulation of KV1.3 channels by protein kinase A I in T lymphocytes is mediated by the disc large 1-tyrosine kinase Lck complex

2012 ◽  
Vol 302 (10) ◽  
pp. C1504-C1512 ◽  
Author(s):  
Zerrin Kuras ◽  
Vladimir Kucher ◽  
Scott M. Gordon ◽  
Lisa Neumeier ◽  
Ameet A. Chimote ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Tyrosine Kinase ◽  
Signaling Pathway ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Scaffolding Protein ◽  
T Cell Function

The cAMP/PKA signaling system constitutes an inhibitory pathway in T cells and, although its biochemistry has been thoroughly investigated, its possible effects on ion channels are still not fully understood. KV1.3 channels play an important role in T-cell activation, and their inhibition suppresses T-cell function. It has been reported that PKA modulates KV1.3 activity. Two PKA isoforms are expressed in human T cells: PKAI and PKAII. PKAI has been shown to inhibit T-cell activation via suppression of the tyrosine kinase Lck. The aim of this study was to determine the PKA isoform modulating KV1.3 and the signaling pathway underneath. 8-Bromoadenosine 3′,5′-cyclic monophosphate (8-BrcAMP), a nonselective activator of PKA, inhibited KV1.3 currents both in primary human T and in Jurkat cells. This inhibition was prevented by the PKA blocker PKI6–22. Selective knockdown of PKAI, but not PKAII, with siRNAs abolished the response to 8-BrcAMP. Additional studies were performed to determine the signaling pathway mediating PKAI effect on KV1.3. Overexpression of a constitutively active mutant of Lck reduced the response of KV1.3 to 8-Br-cAMP. Moreover, knockdown of the scaffolding protein disc large 1 (Dlg1), which binds KV1.3 to Lck, abolished PKA modulation of KV1.3 channels. Immunohistochemistry studies showed that PKAI, but not PKAII, colocalizes with KV1.3 and Dlg1 indicating a close proximity between these proteins. These results indicate that PKAI selectively regulates KV1.3 channels in human T lymphocytes. This effect is mediated by Lck and Dlg1. We thus propose that the KV1.3/Dlg1/Lck complex is part of the membrane pathway that cAMP utilizes to regulate T-cell function.

scholarly journals Empty conformers of HLA-B preferentially bind CD8 and regulate CD8+ T cell function

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Jie Geng ◽  
John D Altman ◽  
Sujatha Krishnakumar ◽  
Malini Raghavan
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Cell Function ◽  
Cd8 T Cell ◽  
Cell Surface Expression ◽  
Antigenic Peptides

When complexed with antigenic peptides, human leukocyte antigen (HLA) class I (HLA-I) molecules initiate CD8+ T cell responses via interaction with the T cell receptor (TCR) and co-receptor CD8. Peptides are generally critical for the stable cell surface expression of HLA-I molecules. However, for HLA-I alleles such as HLA-B*35:01, peptide-deficient (empty) heterodimers are thermostable and detectable on the cell surface. Additionally, peptide-deficient HLA-B*35:01 tetramers preferentially bind CD8 and to a majority of blood-derived CD8+ T cells via a CD8-dependent binding mode. Further functional studies reveal that peptide-deficient conformers of HLA-B*35:01 do not directly activate CD8+ T cells, but accumulate at the immunological synapse in antigen-induced responses, and enhance cognate peptide-induced cell adhesion and CD8+ T cell activation. Together, these findings indicate that HLA-I peptide occupancy influences CD8 binding affinity, and reveal a new set of regulators of CD8+ T cell activation, mediated by the binding of empty HLA-I to CD8.

scholarly journals Hypoxia is a dominant remodeler of the CD8+ T cell surface proteome relative to activation and regulatory T cell-mediated suppression

2021 ◽  
Author(s):  
James Robert Byrnes ◽  
Amy M Weeks ◽  
Julia Carnevale ◽  
Eric Shifrut ◽  
Lisa Kirkemo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Metabolic Reprogramming ◽  
T Cell Function ◽  
Human T Cells ◽  
Surface Proteome

Immunosuppressive factors in the tumor microenvironment (TME) impair T cell function and limit the anti-tumor immune response. T cell surface receptors that influence interactions and function in the TME are already proven targets for cancer immunotherapy. However, surface proteome remodeling of primary human T cells in response to suppressive forces in the TME has never been characterized systematically. Using a reductionist cell culture approach with primary human T cells and SILAC-based quantitative cell surface capture glycoproteomics, we examined how two immunosuppressive TME factors, regulatory T cells (Tregs) and hypoxia, globally affect the activated CD8+ surface proteome (surfaceome). Surprisingly, the CD8+/Treg co-culture only modestly affected the CD8+ surfaceome, but did reverse several activation-induced surfaceomic changes. In contrast, hypoxia dramatically altered the CD8+ surfaceome in a manner consistent with both metabolic reprogramming and induction of an immunosuppressed state. The CD4+ T cell surfaceome similarly responded to hypoxia, revealing a novel hypoxia-induced surface receptor program. Our findings are consistent with the premise that hypoxic environments create a metabolic challenge for T cell activation, which may underlie the difficulty encountered in treating solid tumors with immunotherapies. Together, the data presented here provide insight into how suppressive TME factors remodel the T cell surfaceome and represent a valuable resource to inform future therapeutic efforts to enhance T cell function in the TME.

scholarly journals Differential CD147 Functional Epitopes on Distinct Leukocyte Subsets

2021 ◽  
Vol 12 ◽  
Author(s):  
Supansa Pata ◽  
Sirirat Surinkaew ◽  
Nuchjira Takheaw ◽  
Witida Laopajon ◽  
Kantinan Chuensirikulchai ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Inflammatory Diseases ◽  
Cell Contact ◽  
Cell Functions ◽  
Tnf Α ◽  
Ifn Γ

CD147, a member of the immunoglobulin (Ig) superfamily, is widely expressed in several cell types. CD147 molecules have multiple cellular functions, such as migration, adhesion, invasion, energy metabolism and T cell activation. In particular, recent studies have demonstrated the potential application of CD147 as an effective therapeutic target for cancer, as well as autoimmune and inflammatory diseases. In this study, we elucidated the functional epitopes on CD147 extracellular domains in T cell regulation using specific monoclonal antibodies (mAbs). Upon T cell activation, the anti-CD147 domain 1 mAbs M6-1E9 and M6-1D4 and the anti-CD147 domain 2 mAb MEM-M6/6 significantly reduced surface expression of CD69 and CD25 and T cell proliferation. To investigate whether functional epitopes of CD147 are differentially expressed on distinct leukocyte subsets, PBMCs, monocyte-depleted PBMCs and purified T cells were activated in the presence of anti-CD147 mAbs. The mAb M6-1E9 inhibited T cell functions via activation of CD147 on monocytes with obligatory cell-cell contact. Engagement of the CD147 epitope by the M6-1E9 mAb downregulated CD80 and CD86 expression on monocytes and IL-2, TNF-α, IFN-γ and IL-17 production in T cells. In contrast, the mAb M6-1D4 inhibited T cell function via activation of CD147 on T cells by downregulating IL-2, TNF-α and IFN-γ. Herein, we demonstrated that certain epitopes of CD147, expressed on both monocytes and T cells, are involved in the regulation of T cell activation.

Novel synthetic immune modulators for the activation of tumor antigen-specific T cells.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15203-e15203
Author(s):  
Di Zhang ◽  
Lihua Shi ◽  
Susan Tam ◽  
Man-Cheong Fung
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Tumor Antigen ◽  
Cell Activation ◽  
Checkpoint Inhibitors ◽  
Adoptive T Cell Therapy ◽  
In Vivo Studies ◽  
Target Specificity ◽  
T Cell Therapy

e15203 Background: Although checkpoint inhibitor immunotherapy and adoptive T-cell therapy revolutionized cancer treatments, such approaches suffer either from lack of target specificity for checkpoint inhibitors or inability to target intracellular tumor-related antigens from CAR-T therapy. Here, we report the development of novel Tavo Immune Modulator (TIM) biologics molecules which can specifically recognize tumor antigen-specific T cells through an engineered pMHC complex with peptides derived from intracellular tumor-related antigens. These molecules can selectively activate such T cells through engineered T cell co-stimulatory modulators for enhanced tumor cell killing. Methods: NY-ESO-1 and MAGE-A10 TIM molecules were constructed as fusions of HLA-A*02:01 MHC complexed with either NY-ESO-1 (157-165) or MAGE-A10 (254-262) epitope peptides at the N-termini and various T cell costimulatory modulators at the C-termini of IgG heavy and light chains. TIM molecules were expressed in Expi293 cells and purified by Protein A affinity chromatography. Specific binding of TIM with cancer specific T cells was evaluated by immunostaining. The activation and proliferation of tumor specific CD8+ T cells were confirmed in T cell activation and recall assays. Results: Both NY-ESO-1 and MAGE-A10 specific TIM molecules were generated which recognized corresponding tumor specific T cells. NY-ESO-1 TIM engineered with IL2 could activate NY-ESO-1 specific CD8+ T cell exclusively. Engineering additional T cell costimulatory factors along with IL2 on NY-ESO-1 TIM molecule could further boost T cell proliferation and activation in T cell recall assays. Besides NY-ESO-1, combinations of T cell costimulatory factors with MAGE-A10 TIM molecules enhanced specific T cell activation. Additional in vitro and in vivo studies are ongoing to demonstrate efficacy of such novel TIM molecules in eliminating different types of NY-ESO-1 and MAGE-A10 which are over-expressed on tumor cells. Conclusions: This study demonstrates the utility of NY-ESO-1 and MAGE-A10 TIM molecules in the selective recognition and activation of tumor antigen-specific T cells. Such novel biologics molecules may provide target specificity in tumor treatment, and potential targeting of intracellular tumor-related antigens presented as peptides in MHC complexes on cell surfaces. Selective activation of tumor-specific T cells may provide a unique method for the treatment of various solid tumors and warrants further investigation.

IL-6 Production by B-CLL Cells Plays a Critical Role in the Inhibition of T Cell Activation and Proliferation and Promotes a Th2 Response in Normal T Lymphocytes.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2808-2808 ◽  
Author(s):  
Andrea G.S. Buggins ◽  
Piers E.M. Patten ◽  
Julie Richards ◽  
Stephen J. Orr ◽  
Ghulam J. Mufti ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Critical Role ◽  
Lymphocytic Leukemia ◽  
Th2 Response ◽  
Cytokine Bead Array ◽  
Cd40l Expression

Abstract Immune dysfunction is a hallmark of B-cell chronic lymphocytic leukemia (B-CLL) which occurs through loss of normal cell function as the malignant clone expands, as a result of therapy or because of immunoregulatory properties of the tumor itself. It has previously been shown that B-CLL cells are poor stimulators of the allogeneic mixed lymphocyte reaction (MLR) and we first determined whether this is due to lack of stimulatory activity or active immunosuppression by examining the effect of B-CLL contact and tumor supernatant (TSN) on a 3rd party MLR. Incorporation of B-CLL cells in a 5 day MLR inhibited 3H proliferation by responders in 2/10 cases, whereas TSN inhibited in all 10 cases. Studies in which normal T cells were stimulated by CD3/28 beads for 72 hours in the absence or presence of TSN showed a reduction in cell cycle entry measured by PI and FITC staining with 26+/−4.6% and 13.7+/−4.3% of cells in S +G2M in the absence and presence of TSN respectively (p<0.0001). Studies performed using CFSE labelled normal T cells showed that TSN reduced the number of T cells undergoing one or more cell divisions from a mean of 81.8+/−1.65% to 58.2+/−4.4% (p=0.0072). It is known that T cells in B-CLL have an acquired defect in CD40L expression, which has been ascribed to downregulation by CD40 present on tumor cells. Our experiments confirm that this defect is reversible since purification of B-CLL T cells restores activation induced CD40L upregulation to normal. We further demonstrate that B-CLL TSN from all 17 patients tested inhibits CD40L upregulation by normal T cells in response to PMA and ionomycin or CD3/28 beads (to a mean of 51%+/−5.6%, p<0.0001, of those activated in the absence of TSN) and a parallel inhibition of IL-2 secretion (correlation with CD40L inhibition: p=0.006, r2 = 0.54). In addition to the effects of TSN on T proliferation and activation, B-CLL TSN also induced Th2 polarisation of normal T cells. When activated using CD3/28 beads in control medium, normal T cells show an increase in IL-2, γ-interferon and TNF-α secretion consistent with the expected Th1 response. When incubated in TSN however, 10 and 1000 fold increases in IL-4 and IL6 release were observed respectively consistent with a shift to a Th2 response. B-CLL cells are known to secrete a number of cytokines and in order to determine which might be responsible for the observed effects a number were assayed either by enzyme-linked or cytokine bead array assay. The effects of TSN were not due to TGF-β , IL-10 or soluble CD40 and depletion of soluble CD25 using bead conjugated anti-CD25 had no effect on the immunosuppressive activity. High levels of IL-6 were detected in TSN from all cases studied (n=5). When normal T cell were activated in TSN, a 100 fold further increase in IL-6 level was observed suggesting that this cytokine may be responsible for at least some of the observed effects of TSN. Antibody neutralization of the IL-6 in TSN demonstrated an increase in both Th1 cytokine production and CD40L expression. Furthermore, addition of recombinant IL-6 to T cells activated in media inhibited CD40L upregulation. In summary, B-CLL cells secrete factor(s) which inhibit T cell activation and proliferation and promote Th2 polarisation. These factors might contribute to the disease phenotype by impairing T cell responses to infection, predisposing to autoimmunity and promoting the growth of the malignant clone through the action of IL-6.

Enhanced Interaction Between Hsp90 and Raptor Regulates mTOR Signaling upon T Cell Activation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 674-674 ◽  
Author(s):  
Greg M Delgoffe ◽  
Thomas P. Kole ◽  
Robert J Cotter ◽  
Jonathan Powell
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Mammalian Cells ◽  
Cell Activation ◽  
Cell Function ◽  
Transplant Rejection ◽  
Mammalian Target Of Rapamycin ◽  
Hsp90 Inhibitors ◽  
Proteomic Approach

Abstract Full T cell activation requires antigen recognition (Signal 1) in the context of costimulation (Signal 2). Our group and others have determined that the mammalian Target of Rapamycin (mTOR) plays an important role in integrating costimulatory signals. Specifically, Th1 T cell activation in the absence of mTOR activation leads to tolerance in the form of T cell anergy. mTOR is an evolutionarily-conserved serine/threonine kinase which has been shown to interpret environmental cues in mammalian cells. mTOR is activated by an array of diverse inputs including insulin, amino acids, growth factors and CD28. mTOR signals through two signaling complexes: TORC1 and TORC2. A critical component of TORC1 signaling is the Regulatory Associated Protein of TOR (raptor). One of the central questions in understanding mTOR function is determining how diverse upstream signals can lead to diverse downstream functional consequences. To address this issue in T cells we undertook a proteomic approach to identify novel binding proteins for raptor. Jurkat T cells were either incubated in serum-free media or hyper-activated. Raptor was immunoprecipitated (IP) from the two lysates, separated by SDS-PAGE and silver stained. Next, protein bands that were differentially bound to raptor in the lysates from stimulated versus unstimulated cells were identified. One band located near 90 kDa was excised and using mass spectrometry subsequently determined to be Hsp90, a chaperone protein necessary for the correct folding of many protein “clients”. These findings were next confirmed in primary T cells. Upon activation with anti-CD3 and anti-CD28, IP of raptor led to co-IP of Hsp90 and IP of Hsp90 led to the concomitant precipitation of raptor. To further determine the role of the Hsp90-raptor interaction in T cells we used 17-AAG, an Hsp90 inhibitor. Primary T cells were stimulated in the presence of rapamycin or 17-AAG. Incubation with 17-AAG but not rapamycin led to a decrease in raptor protein levels consistent with the concept that raptor is an Hsp90 client. Functionally, this led to a decrease in TORC1 activation as measured by phosphorylation of S6K-1. More importantly, although17-AAG did not inhibit IL-2 production upon initial stimulation, primary T cells stimulated with anti-CD3 and anti-CD28 in the presence of 17-AAG failed to produce IL-2 upon rechallenge 5 days later; they were anergic. Overall, our findings demonstrate a novel activation-induced interaction between Hsp90 and raptor in T cells. This interaction can regulate the decision between TCR-induced activation and tolerance. Hsp90 inhibitors are currently being evaluated as anti-neoplastic agents, and while such agents do not acutely inhibit T cell function, they may induce anergy in activated Th1 cells. Thus, Hsp90 inhibitors might be incorporated into novel immunosuppressive regimens to treat and prevent GVHD and transplant rejection through the promotion of T cell tolerance.

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