THEMIS is a priming substrate of non-receptor tyrosine phosphatase PTPN6/SHP1 and plays dual roles during T cell development

THEMIS plays an indispensable role in T cells, but its mechanism of action is highly controversial. Using the systematic proximity labeling methodology PEPSI, we identified THEMIS as an uncharacterized substrate for the phosphatase SHP1. Saturated mutagenesis analysis revealed that THEMIS phosphorylation at the evolutionally conserved Tyr34 residue was oppositely regulated by SHP1 and the kinase LCK. Like THEMIS-/- mice, THEMIS Y34F/Y34F knock-in mice showed a significant decrease in CD4 thymocytes and mature CD4 T cells, but a normal thymic development and peripheral homeostasis of CD8 T cells. Mechanistically, phosphorylated THEMIS induced by TCR activation acts as a "priming substrate" to bind SHP1 and convert its phosphatase activity from basal level to nearly fully activated level, ensuring an appropriate negative regulation of TCR signaling. However, cytokine signaling in CD8 T cells failed to elicit THEMIS Y34 phosphorylation, revealing both phosphorylation-dependent and -independent roles of THEMIS in controlling T cell maturation and expansion.

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The mTOR Pathway Inhibits Expression of the Tumor Suppressors ELF4 and KLF4 Downstream of TCR Signaling to Induce T Cell Proliferation.

Blood ◽

10.1182/blood.v114.22.3688.3688 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3688-3688

Author(s):

Takeshi Yamada ◽

Kirsten Gierach ◽

H. Daniel Lacorazza

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd8 T Cells ◽

Cell Activation ◽

Conflicts Of Interest ◽

T Cell Proliferation ◽

Tcr Signaling ◽

Tcr Activation

Abstract Abstract 3688 Poster Board III-624 Quiescence of circulating naïve T cells is maintained by the transcription factors ELF4 and KLF4 downstream of T-cell receptor (TCR) signaling. Hence, loss of ELF4 leads to increased proliferation of CD8+ T cells in response to homeostatic and antigen driven stimuli (Yamada et al, Nature Immunology, 2009). The identification of signals that suppress this restraint of proliferation will aid to enhance immunological memory during vaccination and to better understand development of T-cell acute lymphoblastic leukemias. Consistent with lower threshold of activation by ELF4 deletion in unstimulated naïve T cells, we identified a significant downregulation of the dual-specificity phosphatases DUSP1 and DUSP5 in a global gene expression study, which was confirmed at a protein level. Consequently, Elf4−/− CD8 T cells showed sustained phosphorylation of Erk1/2 upon TCR activation. In addition, we found that the PD98059 and LY294002 inhibitors, but not Cyclosporin A, blocked inhibition of ELF4 transcription upon TCR activation independently of CD28 co-stimulation and signals emanating from IL-2R. Furthermore, rapamycin also prevented downregulation of ELF4 transcripts following T cell activation, suggesting that mTORC1 inhibits ELF4 transcription downstream of MAPK and PI3K/Akt pathways. We conclude that the transcription factor ELF4 sets a proliferation threshold in naïve T cells by activating DUSPs and that ELF4 suppression upon TCR activation is mediated by mTORC1 downstream of MAPK and PI3K/Akt pathways. Our findings provide important targets of this novel control of T cell proliferation to enhance immune response to vaccination and to prevent expansion of pre-leukemic clones in pediatric patients that fail to respond to current therapies. Disclosures: No relevant conflicts of interest to declare.

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HDAC3 restrains CD8-lineage genes to maintain a bi-potential state in CD4+CD8+ thymocytes for CD4-lineage commitment

eLife ◽

10.7554/elife.43821 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 3

Author(s):

Rachael Laura Philips ◽

Jeong-Heon Lee ◽

Krutika Gaonkar ◽

Pritha Chanana ◽

Ji Young Chung ◽

...

Keyword(s):

T Cells ◽

Mhc Class Ii ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Lineage Commitment ◽

Cytokine Signaling ◽

Rna Seq ◽

Kinetics Analysis ◽

Tcr Signaling ◽

Histone Deacetylase 3

CD4 and CD8 T cells are vital components of the immune system. We found that histone deacetylase 3 (HDAC3) is critical for the development of CD4 T cells, as HDAC3-deficient DP thymocytes generate only CD8SP thymocytes in mice. In the absence of HDAC3, MHC Class II-restricted OT-II thymocytes are redirected to the CD8 cytotoxic lineage, which occurs with accelerated kinetics. Analysis of histone acetylation and RNA-seq reveals that HDAC3-deficient DP thymocytes are biased towards the CD8 lineage prior to positive selection. Commitment to the CD4 or CD8 lineage is determined by whether persistent TCR signaling or cytokine signaling predominates, respectively. Despite elevated IL-21R/γc/STAT5 signaling in HDAC3-deficient DP thymocytes, blocking IL-21R does not restore CD4 lineage commitment. Instead, HDAC3 binds directly to CD8-lineage promoting genes. Thus, HDAC3 is required to restrain CD8-lineage genes in DP thymocytes for the generation of CD4 T cells.

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Themis-associated phosphatase activity controls signaling in T cell development

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1720209115 ◽

2018 ◽

Vol 115 (48) ◽

pp. E11331-E11340 ◽

Cited By ~ 9

Author(s):

Monika Mehta ◽

Joanna Brzostek ◽

Elijah W. Chen ◽

Desmond W. H. Tung ◽

Shuting Chen ◽

...

Keyword(s):

T Cell ◽

Phosphatase Activity ◽

Ex Vivo ◽

Tyrosine Phosphatase ◽

Cell Receptor ◽

Conditional Knockout ◽

Negative Regulator ◽

Tcr Signaling ◽

Thymic Development ◽

Double Deletion

Thymocyte-expressed molecule involved in selection (Themis) has been shown to be important for T cell selection by setting the threshold for positive versus negative selection. Themis interacts with the protein tyrosine phosphatase (PTP) Src-homology domain containing phosphatase-1 (Shp1), a negative regulator of the T cell receptor (TCR) signaling cascade. However, how Themis regulates Shp1 is still not clear. Here, using a very sensitive phosphatase assay on ex vivo thymocytes, we have found that Themis enhances Shp1 phosphatase activity by increasing its phosphorylation. This positive regulation of Shp1 activity by Themis is found in thymocytes, but not in peripheral T cells. Shp1 activity is modulated by different affinity peptide MHC ligand binding in thymocytes. Themis is also associated with phosphatase activity, due to its constitutive interaction with Shp1. In the absence of Shp1 in thymocytes, Themis interacts with Shp2, which leads to almost normal thymic development in Shp1 conditional knockout (cKO) mice. Double deletion of both Themis and Shp1 leads to a thymic phenotype similar to that of Themis KO. These findings demonstrate unequivocally that Themis positively regulates Shp1 phosphatase activity in TCR-mediated signaling in developing thymocytes.

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Separation of Gvhd from GVL Responses By Modulation of TCR Signaling

Blood ◽

10.1182/blood.v124.21.3822.3822 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3822-3822

Author(s):

Mobin Karimi ◽

Martha Jordon ◽

Taku Kambayashi

Keyword(s):

Bone Marrow ◽

T Cells ◽

T Cell ◽

Mouse Model ◽

Tumor Growth ◽

Cd8 T Cells ◽

Leukemia Cells ◽

Cell Phenotype ◽

Tcr Signaling ◽

Allogeneic Hsct

Abstract In allogeneic hematopoietic stem cell transplantation (HSCT), devising new strategies to separate GVHD and GVL responses is of critical importance. However, this is a difficult task, as GVHD and GVL rely on the same recognition of allogeneic MHC by donor-derived T cells. CD8+ T cells are key effector cells that mediate both GVHD and GVL. In mouse models of allogeneic HSCT, the infusion of donor-derived CD8+ T cells eliminates tumor growth but also causes severe GVHD. The activation of CD8+ T cells can be potentially manipulated by perturbing the signaling pathways downstream of the T cell receptor (TCR). TCR signaling depends on the formation of a proximal multimolecular complex, which is nucleated by adaptor proteins such as SLP-76. The phosphorylation of the Y145 residue of SLP-76 is critical for activation of the downstream enzyme PLCg1. As such, a YàF mutation at Y145 of SLP-76 (Y145F) causes decreased TCR-mediated signaling and attenuated T cell function. Here, we investigated how the SLP-76 Y145F mutation in CD8+T cells may impact GVHD and GVL responses in a mouse model of allogeneic HSCT. We employed a major MHC-mismatch mouse model of GVHD involving the transplantation of C57BL/6 (B6)-derived bone marrow (BM) into lethally irradiated Balb/c mice (B6àBalb/c). BM-transplanted mice were also injected with FACS-sorted CD8+ T cells either B6 wildtype (WT) mice or Y145F mice. Recipients of Y145F CD8+ T cells showed significantly (p<0.001) less weight loss, lower clinical score, and improved survival compared to mice injected with WT CD8+ T cells. Next, to determine whether the Y145F CD8+ T cells could mediate GVL effects, BM-transplanted Balb/c mice were additionally challenged intravenously with 1 x 105 luciferase-positive A20 leukemia cells. As expected, BM-transplanted Balb/c mice succumbed from A20 tumor growth, whereas mice injected with WT CD8+ T cells cleared the tumor but developed GVHD. Surprisingly, mice receiving Y145F CD8+ T cells eradicated the leukemic cells but did not develop GVHD. These data suggest that the Y145F mutation in CD8+T cells may be able to separate GVHD from GVL effects. In addition to defective TCR signaling observed in peripheral T cells of Y145F mice, a majority of Y145F KI CD8+ T cells adopt a memory-like CD44hi phenotype through exposure to high levels of IL-4 produced in the thymus of these mice. To test whether the CD44hi CD8+ T cell phenotype was necessary and/or sufficient for the separation of GVHD and GVL effects, BM-transplanted Balb/c mice were injected with FACS-sorted CD44hi or CD44lo CD8+ T cells from WT or Y145F KI mice and challenged with A20 leukemia cells. While BM-transplanted mice receiving CD44hi CD8+ T cells from Y145F mice displayed intact GVL responses without causing GVHD, mice injected with CD44lo CD8+ T cells from Y145F mice displayed impaired ability to clear the tumor cells. Moreover, recipients of CD44hi or CD44lo CD8+ T cells from WT mice cleared the tumor but exhibited severe GVHD. These findings were corroborated with data obtained with an inducible system, whereby CD8+ T cells are affected by the Y145F mutation only after full maturation and thus do not display a CD44hi phenotype (Y145F conditional knock-in mice). Bone marrow-transplanted recipients receiving Y145F conditional knock-in CD8+ T cells developed GVHD and exhibited an attenuated GVL response, suggesting that the Y145F mutation needed to be present during T cell development. Together, these data suggest that either the Y145F mutation or CD44hi phenotype alone in CD8+T cells is insufficient to separate GVHD from GVT. Our data demonstrate that perturbation of the TCR signaling pathway downstream of Y145 of SLP-76 in CD8+ T cells results in separation of GVHD from GVL effects. Experiments to mechanistically test how the Y145F signaling mutation synergizes with the CD44hi phenotype of CD8+ T cells to allow for the separation of the GVHD and GVL effects are currently underway. Our novel and unexpected finding could lead to a novel therapeutic strategy for treatment of acute GVHD after allogeneic HSCT. Disclosures No relevant conflicts of interest to declare.

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Kindlin-3 is required for the stabilization of TCR-stimulated LFA-1:ICAM-1 bonds critical for lymphocyte arrest and spreading on dendritic cells

Blood ◽

10.1182/blood-2010-12-322859 ◽

2011 ◽

Vol 117 (26) ◽

pp. 7042-7052 ◽

Cited By ~ 33

Author(s):

Sara W. Feigelson ◽

Valentin Grabovsky ◽

Eugenia Manevich-Mendelson ◽

Ronit Pasvolsky ◽

Ziv Shulman ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Leukocyte Adhesion ◽

Lymphocyte Function ◽

Leukocyte Adhesion Deficiency ◽

Tcr Signaling ◽

Normal Expression ◽

Lymphocyte Motility ◽

Tcr Activation

Kindlin-3 is a key lymphocyte function–associated antigen-1 (LFA-1) coactivator deleted in leukocyte adhesion deficiency-III (LAD-III). In the present study, we investigated the involvement of this adaptor in lymphocyte motility and TCR-triggered arrest on ICAM-1 or on dendritic cells (DCs). Kindlin-3–null primary T cells from a LAD-III patient migrated normally on the major lymph node chemokine CCL21 and engaged in normal TCR signaling. However, TCR activation of Kindlin-3–null T lymphocytes failed to trigger the robust LFA-1–mediated T-cell spreading on ICAM-1 and ICAM-1–expressing DCs that is observed in normal lymphocytes. Kindlin-3 was also essential for cytoskeletal anchorage of the LFA-1 heterodimer and for microclustering of LFA-1 within ventral focal dots of TCR-stimulated lymphocytes spread on ICAM-1. Surprisingly, LFA-1 on Kindlin-3–null lymphocytes migrating over CCL21 acquired normal expression of an epitope associated with the conformational activation of the key headpiece domain, β I. This activated LFA-1 was highly responsive to TCR-triggered ICAM-1–driven stop signals in normal T cells locomoting on CCL21, but not in their Kindlin-3–null T-cell counterparts. We suggest that Kindlin-3 selectively contributes to a final TCR-triggered outside-in stabilization of bonds generated between chemokine-primed LFA-1 molecules and cell-surface ICAM-1.

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CD45 functions as a signaling gatekeeper in T cells

Science Signaling ◽

10.1126/scisignal.aaw8151 ◽

2019 ◽

Vol 12 (604) ◽

pp. eaaw8151 ◽

Cited By ~ 8

Author(s):

Adam H. Courtney ◽

Alexey A. Shvets ◽

Wen Lu ◽

Gloria Griffante ◽

Marianne Mollenauer ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Tcr Signaling ◽

Downstream Signaling ◽

High Affinity ◽

Signaling Events ◽

Genetic Perturbations ◽

Computational Analyses

T cells require the protein tyrosine phosphatase CD45 to detect and respond to antigen because it activates the Src family kinase Lck, which phosphorylates the T cell antigen receptor (TCR) complex. CD45 activates Lck by opposing the negative regulatory kinase Csk. Paradoxically, CD45 has also been implicated in suppressing TCR signaling by dephosphorylating the same signaling motifs within the TCR complex upon which Lck acts. We sought to reconcile these observations using chemical and genetic perturbations of the Csk/CD45 regulatory axis incorporated with computational analyses. Specifically, we titrated the activities of Csk and CD45 and assessed their influence on Lck activation, TCR-associated ζ-chain phosphorylation, and more downstream signaling events. Acute inhibition of Csk revealed that CD45 suppressed ζ-chain phosphorylation and was necessary for a regulatable pool of active Lck, thereby interconnecting the activating and suppressive roles of CD45 that tune antigen discrimination. CD45 suppressed signaling events that were antigen independent or induced by low-affinity antigen but not those initiated by high-affinity antigen. Together, our findings reveal that CD45 acts as a signaling “gatekeeper,” enabling graded signaling outputs while filtering weak or spurious signaling events.

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A Point Mutation in the Juxtamembrane Wedge of CD45 Impacts Myeloid Development and Generates a Novel Model for Hemophagocytic Disorders in the Context of a MHC I-Restricted Transgene.

Blood ◽

10.1182/blood.v110.11.317.317 ◽

2007 ◽

Vol 110 (11) ◽

pp. 317-317 ◽

Cited By ~ 1

Author(s):

Michelle L. Hermiston ◽

Fleur R. de Graaf ◽

Art Weiss

Keyword(s):

T Cells ◽

T Cell ◽

Point Mutation ◽

Cd8 T Cells ◽

Adoptive Transfer ◽

Macrophage Activation ◽

Tyrosine Phosphatase ◽

Myeloid Cell ◽

Premature Death ◽

Regulatory Function

Abstract The receptor like-protein tyrosine phosphatase CD45 is highly expressed on all nucleated hematopoietic cells and functions by modulating the activity of Src family kinases. We previously generated mice containing a point mutation in the juxtamembrane wedge of CD45 that leads to constitutive phosphatase activity. Demonstrating the critical negative regulatory function of the wedge, the CD45E613R mutation led to a lymphoproliferative disorder, lupus-like autoimmune syndrome, and premature death at 9–12 months of age. To address the intrinsic effects of the wedge mutation on the CD8 T cell lineage, we introduced a CD8 restricted T-cell receptor (TCR) transgene, OT1, specific for the antigen ovalbumin, into CD45E613R mice. Surprisingly, 100% of the CD45E613R/OT1+ mice succumb by 6 weeks of age to a rapidly progressive disease characterized by severe cachexia, hemophagocytosis, and markedly elevated interferon gamma levels. This phenotype shares similarity to the human hemophagocytic syndromes hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS). The aims of this study are to identify the mechanistic basis and the cell type(s) responsible for this phenotype. Using a genetic approach, we demonstrate that the phenotype is maintained in CD45E613R/OT1+mice on a Rag1−/− background, thus implicating myeloid and/or CD8 T cells in disease pathogenesis. Analysis of myeloid cell development, phagocytic function, and signaling indicate that the wedge mutation operates in this lineage. Despite the intrinsic hyperresponsiveness of CD45E613R macrophages, adoptive transfer experiments demonstrate they are not essential for disease. However, adoptive transfer of purified CD45E613R/OT1+ CD8 T cells into either CD45 mutant or CD45 wildtype (wt) is sufficient to initiate disease. Interestingly, CD45E613R CD8 OT+ T cells are not dominant over CD45wt CD8+ cells. In addition we show that transfer of CD45wt CD8+ T cells into ill mice can delay disease progression. We hypothesize that, in the setting of the wedge mutation, the restricted repertoire of the CD8 T cells in CD45E613R/OT1+ mice might not be able to limit macrophage activation. We believe these mice may represent a useful model for understanding the molecular pathogenesis of hemophagocytic disorders, devastating and often fatal diseases in humans.

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498 Downregulation of CD5 in CD8+ T tumour-infiltrating lymphocytes associates with increased level of activation and exhaustion

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0498 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A533-A533

Author(s):

Faizah Alotaibi ◽

Mark Vincent ◽

Weiping Min ◽

James Koropatnick

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd8 T Cells ◽

Cell Activation ◽

Ex Vivo ◽

Cd8 T Cell ◽

Tcr Signaling ◽

Peripheral Organs ◽

Infiltrating Lymphocytes

BackgroundCD5, a member of the scavenger receptor cysteine-rich superfamily, is a marker for T cells and a subset of B cells (B1a). CD5 associates with T-cell and B-cell receptors and impair TCR signaling1 2 and increased CD5 is an indication of B cell activation. Furthermore, CD5 levels on CD8+ T cell splenocytes were significantly increased after TCR/CD3 stimulation using ex vivo treatment with anti-CD3/anti-CD28 MAbs compared to non-stimulated CD8+ T splenocytes.3 Previous studies have shown a correlation between CD5 and anti-tumour immunity where CD5 knockout mice inoculated with B16F10 melanoma cells had delayed tumour growth compared to wild type mice.4 In tumour-infiltrating lymphocytes (TILs) isolated from lung cancer patients, CD5 levels were negatively correlated with anti-tumour activity and tumour-mediated activation-induced T cell death,5 suggesting that CD5 could impair activation of anti-tumour T cells. However, the correlation between CD5 level expression and T cell activation and exhaustion in the tumour microenvironment and in peripheral organs is ill-defined and requires further investigation.MethodsWe determined CD5 levels in T cell subsets in different organs in mice bearing syngeneic 4T1 breast tumour homografts and assessed the relationship between CD5 and increased CD69 and PD-1 (markers of T cell activation and exhaustion) by flow cytometry.ResultsWe report that T cell CD5 levels were higher in CD4+ T cells than in CD8+ T cells in 4T1 tumour-bearing mice, and that high CD5 levels on CD4+ T cells were maintained in peripheral organs (spleen and lymph nodes). However, both CD4+ and CD8+ T cells recruited to tumours had reduced CD5 compared to CD4+ and CD8+ T cells in peripheral organs. In addition, CD5highCD4+ T cells and CD5highCD8+ T cells from peripheral organs exhibited higher levels of activation and associated exhaustion compared to CD5lowCD4+ T cell and CD5lowCD8+ T cell from the same organs. Interestingly, CD8+ T cells among TILs and downregulated CD5 were activated to a higher level, with concomitantly increased exhaustion markers, than CD8+CD5+ TILs.ConclusionsThus, differential CD5 levels among T cells in tumours and lymphoid organs can be associated with different levels of T cell activation and exhaustion, suggesting that CD5 may be a therapeutic target for immunotherapeutic activation in cancer therapy.AcknowledgementsThe author thanks Rene Figueredo and Ronak Zareardalan for their assistance in animal workEthics ApprovalThis study was approved by the Animal Use Subcommittee of the University of Western OntarioReferencesAzzam HS, et al., Fine tuning of TCR signaling by CD5. The Journal of Immunology 2001. 166(9): p. 5464–5472.Voisinne GA, Gonzalez de Peredo and Roncagalli R. CD5, an undercover regulator of TCR signaling. Frontiers in Immunology 2018;9:p. 2900.Alotaibi, F., et al., CD5 blockade enhances ex vivo CD8+ T cell activation and tumour cell cytotoxicity. European journal of immunology 2020;50(5): p. 695–704.Tabbekh, M., et al., Rescue of tumor-infiltrating lymphocytes from activation-induced cell death enhances the antitumor CTL response in CD5-deficient mice. The Journal of Immunology, 2011. 187(1): p. 102–109.Dorothée, G., et al., In situ sensory adaptation of tumor-infiltrating T lymphocytes to peptide-MHC levels elicits strong antitumor reactivity. The Journal of Immunology 2005;174(11): p. 6888–6897.

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miR-155 augments CD8+ T-cell antitumor activity in lymphoreplete hosts by enhancing responsiveness to homeostatic γc cytokines

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1422916112 ◽

2014 ◽

Vol 112 (2) ◽

pp. 476-481 ◽

Cited By ~ 61

Author(s):

Yun Ji ◽

Claudia Wrzesinski ◽

Zhiya Yu ◽

Jinhui Hu ◽

Sanjivan Gautam ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Tyrosine Phosphatase ◽

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling ◽

Akt Activation ◽

Effector Functions ◽

Life Threatening ◽

A Cell ◽

Protein Kinase Akt

Lymphodepleting regimens are used before adoptive immunotherapy to augment the antitumor efficacy of transferred T cells by removing endogenous homeostatic “cytokine sinks.” These conditioning modalities, however, are often associated with severe toxicities. We found that microRNA-155 (miR-155) enabled tumor-specific CD8+ T cells to mediate profound antitumor responses in lymphoreplete hosts that were not potentiated by immune-ablation. miR-155 enhanced T-cell responsiveness to limited amounts of homeostatic γc cytokines, resulting in delayed cellular contraction and sustained cytokine production. miR-155 restrained the expression of the inositol 5-phosphatase Ship1, an inhibitor of the serine-threonine protein kinase Akt, and multiple negative regulators of signal transducer and activator of transcription 5 (Stat5), including suppressor of cytokine signaling 1 (Socs1) and the protein tyrosine phosphatase Ptpn2. Expression of constitutively active Stat5a recapitulated the survival advantages conferred by miR-155, whereas constitutive Akt activation promoted sustained effector functions. Our results indicate that overexpression of miR-155 in tumor-specific T cells can be used to increase the effectiveness of adoptive immunotherapies in a cell-intrinsic manner without the need for life-threatening, lymphodepleting maneuvers.

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SOCS-1 regulates IL-15–driven homeostatic proliferation of antigen-naive CD8 T cells, limiting their autoimmune potential

Journal of Experimental Medicine ◽

10.1084/jem.20050003 ◽

2005 ◽

Vol 202 (8) ◽

pp. 1099-1108 ◽

Cited By ~ 52

Author(s):

Gayle M. Davey ◽

Robyn Starr ◽

Ann L. Cornish ◽

J. Theodore Burghardt ◽

Warren S. Alexander ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Disease Onset ◽

Cell Receptor ◽

Interferon Γ ◽

Cytokine Signaling ◽

Cell Repertoire ◽

Homeostatic Expansion ◽

Deficient Mice

Mice that are deficient in suppressor of cytokine signaling–1 (SOCS-1) succumb to neonatal mortality that is associated with extensive cellular infiltration of many tissues. T cells seem to be necessary for disease, which can be alleviated largely by neutralizing interferon-γ. Examining T cell receptor (TCR) specificity shows that even monospecific T cells can mediate disease in SOCS-1–deficient mice, although disease onset is substantially faster with a polyclonal T cell repertoire. A major phenotype of SOCS-1−/− mice is the accumulation of CD44highCD8+ peripheral T cells. We show that SOCS-1–deficient CD8, but not CD4, T cells proliferate when transferred into normal (T cell–sufficient) mice, and that this is dependent on two signals: interleukin (IL)-15 and self-ligands that are usually only capable of stimulating homeostatic expansion in T cell–deficient mice. Our findings reveal that SOCS-1 normally down-regulates the capacity of IL-15 to drive activation and proliferation of naive CD8 T cells receiving TCR survival signals from self-ligands. We show that such dysregulated proliferation impairs the deletion of a highly autoreactive subset of CD8 T cells, and increases their potential for autoimmunity. Therefore, impaired deletion of highly autoreactive CD8 T cells, together with uncontrolled activation of naive CD8 T cells by homeostatic survival ligands, may provide a basis for the T cell–mediated disease of SOCS-1−/− mice.

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