Regulation of T Cell Homeostasis by the Transmembrane Adaptor Protein SIT

Posevitz, Vilmos; Arndt, Boerge; Krieger, Tina; Warnecke, Nicole; Schraven, Burkhart; Simeoni, Luca

doi:10.4049/jimmunol.180.3.1634

Cited by 19 publications

(29 citation statements)

References 54 publications

(58 reference statements)

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“…Therefore, we propose that these adaptors may regulate homeostatic signals, which are induced by lowaffinity self-ligands rather those that are induced by high-avidity foreign antigens. This hypothesis is supported by our previous observations showing that SIT negatively regulates T cell homeostasis and inhibits TCR-mediated signaling induced by weak but not strong stimuli [8,9] How SIT and LAX together regulate TCR-mediated signaling remains still elusive. A major obstacle in the analysis of the biochemical events that are regulated by SIT and LAX is the development of sensory adaptation upon loss of SIT.…”

Section: Discussionsupporting

confidence: 75%

“…This means that the activation threshold of SIT Ϫ/Ϫ T cells is elevated, leading to reduced responsiveness upon TCR engagement. In fact, we have shown previously that SIT Ϫ/Ϫ T lymphocytes up-regulate CD5, a molecule required to reprogram the activation threshold in response to an altered signaling strength, and negatively regulate TCR-mediated signals, downegulate the coreceptor CD8, and display impaired ZAP-70 activation and TCR -chain phosphorylation [8]. It appears that compensatory mechanisms are set in motion also in double mutant mice, as similarly to SIT Ϫ/Ϫ T cells, T cells from DKO mice also up-regulate CD5 and are hyporesponsive to strong TCR stimulation (data not shown and Supplemental Fig.…”

Section: Discussionmentioning

confidence: 99%

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Cooperative immunoregulatory function of the transmembrane adaptor proteins SIT and LAX

Arndt

Kalinski

Reinhold

et al. 2013

Journal of Leukocyte Biology

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Lymphocyte activation is crucial for the generation of immune responses. In vitro studies have demonstrated that TRAPs are critical regulators of lymphocyte activation. However, more recent in vivo studies have demonstrated that with the exception of LAT, TRAPs, such as SIT, NTAL, and LAX, only minimally affect immune cell functions. Additional studies have suggested that the mild or the apparent lack of a phenotype displayed by most TRAP KO mice may be explained by functional redundancy among this family of adaptors. In fact, it has been shown that the phenotype of NTAL/LAT or SIT/TRIM double-deficient mice is more severe than that of the single KOs. Here, we have evaluated whether SIT and the related transmembrane adaptor LAX have overlapping functions by generating SIT/LAX DKO mice. We show that DKO, in contrast to single KO mice, accumulate large numbers of activated CD4 ϩ T cells in the spleen. Moreover, conventional B cells from DKO mice are hyperproliferative upon CD40 stimulation. Additionally, we found that DKO mice displayed an expansion of the B1 cell pool in the peritoneal cavity, hypergammaglobulinaemia, and an enhanced immune response to the T1-independent antigen, TNP-LPS. Finally, we demonstrate that SIT/LAX double deficiency resulted in a more pronounced breakdown of peripheral tolerance and the development of autoimmunity characterized by ANAs and renal disease (glomerulonephritis and proteinuria). Collectively, our data indicate that SIT and LAX are important negative regulators of immune responses that functionally cooperate.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Cooperative immunoregulatory function of the transmembrane adaptor proteins SIT and LAX

Arndt

Kalinski

Reinhold

et al. 2013

Journal of Leukocyte Biology

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“…3D). These data are in agreement with our recent observation demonstrating that the loss of SIT markedly enhanced the homeostatic expansion of peripheral T3.70 ϩ T cells from HY transgenic female mice (39).…”

Section: Conversion From Positive To Negative Selection In Dko Micesupporting

confidence: 83%

SIT and TRIM Determine T Cell Fate in the Thymus

Koelsch

Schraven²,

Simeoni³

2008

The Journal of Immunology

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Thymic selection is a tightly regulated developmental process essential for establishing central tolerance. The intensity of TCR-mediated signaling is a key factor for determining cell fate in the thymus. It is widely accepted that low-intensity signals result in positive selection, whereas high-intensity signals induce negative selection. Transmembrane adaptor proteins have been demonstrated to be important regulators of T cell activation. However, little is known about their role during T cell development. Herein, we show that SIT (SHP2 Src homology domain containing tyrosine phosphatase 2-interacting transmembrane adaptor protein) and TRIM (TCR-interacting molecule), two structurally related transmembrane adaptors, cooperatively regulate TCR signaling potential, thereby influencing the outcome of thymic selection. Indeed, loss of both SIT and TRIM resulted in the up-regulation of CD5, CD69, and TCRβ, strong MAPK activation, and, consequently, enhanced positive selection. Moreover, by crossing SIT/TRIM double-deficient mice onto transgenic mice bearing TCRs with different avidity/affinity, we found profound alterations in T cell development. Indeed, in female HY TCR transgenic mice, positive selection was completely converted into negative selection resulting in small thymi devoided of double-positive thymocytes. More strikingly, in a nonselecting background, SIT/TRIM double-deficient single-positive T cells developed, were functional, and populated the periphery. In summary, we demonstrated that SIT and TRIM regulate cell fate of developing thymocytes, thus identifying them as essential regulators of central tolerance.

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“…5a). The lack of fast-paced LIP in T cells bearing transgenic TCRs has been reported previously, but the basis for this remains unclear 6,10,39 . Although OT-I T cells exhibited greater TCR affinity/avidity when compared with P14 T cells (as indicated by CD5 levels), there were no significant differences in PTPN2 levels (Fig.…”

Section: Ptpn2 Deficiency Enhances Tcr-dependent Lipmentioning

confidence: 97%

PTPN2 attenuates T-cell lymphopenia-induced proliferation

2014

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When the peripheral T-cell pool is depleted, T cells undergo homoeostatic expansion. This expansion is reliant on the recognition of self-antigens and/or cytokines, in particular interleukin-7. The T cell-intrinsic mechanisms that prevent excessive homoeostatic T-cell responses and consequent overt autoreactivity remain poorly defined. Here we show that protein tyrosine phosphatase N2 (PTPN2) is elevated in naive T cells leaving the thymus to restrict homoeostatic T-cell proliferation and prevent excess responses to self-antigens in the periphery. PTPN2-deficient CD8 þ T cells undergo rapid lymphopenia-induced proliferation (LIP) when transferred into lymphopenic hosts and acquire the characteristics of antigenexperienced effector T cells. The enhanced LIP is attributed to elevated T-cell receptordependent, but not interleukin-7-dependent responses, results in a skewed T-cell receptor repertoire and the development of autoimmunity. Our results identify a major mechanism by which homoeostatic T-cell responses are tuned to prevent the development of autoimmune and inflammatory disorders.

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Regulation of T Cell Homeostasis by the Transmembrane Adaptor Protein SIT

Cited by 19 publications

References 54 publications

Cooperative immunoregulatory function of the transmembrane adaptor proteins SIT and LAX

Cooperative immunoregulatory function of the transmembrane adaptor proteins SIT and LAX

SIT and TRIM Determine T Cell Fate in the Thymus

PTPN2 attenuates T-cell lymphopenia-induced proliferation

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