Reduced TCR signaling potential impairs negative selection but does not result in autoimmune disease

Song, Ki-Duk; Lesourne, Renaud; Lee, Jan; Pinkhasov, Julia; Li, LiQi; El-Khoury, Dalal; Love, Paul E.

doi:10.1084/jem.20120058

Cited by 47 publications

(63 citation statements)

References 59 publications

(105 reference statements)

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“…Therefore, it is possible that dysregulation of both positive and negative selection in SATB1cKO mice is also caused by weak TCR signal strength at the DP stage. However, it has been reported that symptoms of autoimmune diseases are not observed in TCRz mutant mice because of increased numbers of Foxp3 + Treg cells (53). SATB1cKO mice have impairment of Treg functions compared with WT mice at adulthood (Fig.…”

Section: Discussionmentioning

confidence: 97%

SATB1 Plays a Critical Role in Establishment of Immune Tolerance

Kondo

Tanaka

Kuwabara

et al. 2016

The Journal of Immunology

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Special AT-rich sequence binding protein 1 (SATB1) is a genome organizer that is expressed by T cells. T cell development is severely impaired in SATB1 null mice; however, because SATB1 null mice die by 3 wk of age, the roles of SATB1 in T cell development have not been well clarified. In this study, we generated and analyzed SATB1 conditional knockout (cKO) mice, in which the SATB1 gene was deleted from all hematopoietic cells. T cell numbers were reduced in these mice, mainly because of a deficiency in positive selection at the CD4+CD8+ double-positive stage during T cell development in the thymus. We also found that SATB1 cKO mice developed autoimmune diseases within 16 wk after birth. In SATB1 cKO mice, the numbers of Foxp3+ regulatory T (Treg) cells were significantly reduced at 2 wk of age compared with wild-type littermates. Although the numbers gradually increased upon aging, Treg cells in SATB1 cKO mice were still less than those in wild-type littermates at adulthood. Suppressive functions of Treg cells, which play a major role in establishment of peripheral tolerance, were also affected in the absence of SATB1. In addition, negative selection during T cell development in the thymus was severely impaired in SATB1 deficient mice. These results suggest that SATB1 plays an essential role in establishment of immune tolerance.

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Section: Discussionmentioning

confidence: 97%

SATB1 Plays a Critical Role in Establishment of Immune Tolerance

Kondo

Tanaka

Kuwabara

et al. 2016

The Journal of Immunology

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“…6A, 6C, 6E, 6F). A very recent study (48) of mutant CD3z-chain knockin mice indicated that attenuation of TCR proximal signaling disproportionately impairs downstream signaling responses and subsequently favors Foxp3 expression and T reg lineage commitment. Consistent with this result, in our study, additional expression of transgenic Pep attenuated TCR proximal signaling and downstream Akt and Foxo1 activation in T cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

Different Modulation of Ptpn22 in Effector and Regulatory T Cells Leads to Attenuation of Autoimmune Diabetes in Transgenic Nonobese Diabetic Mice

Yeh

Miaw

Lin

et al. 2013

The Journal of Immunology

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Ptpn22 encodes PEST domain–enriched tyrosine phosphatase (Pep), which negatively regulates TCR proximal signaling and is strongly associated with a variety of autoimmune diseases in humans. The net effect of Pep on the balance of immunity and tolerance is uncertain because of the simultaneous inhibition of TCR-mediated signaling of effector and regulatory T cells (Tregs). In this study, we generated transgenic NOD mice that overexpressed Pep in T cells. The transgenic mice had a significantly lower incidence of spontaneous autoimmune diabetes, which was accompanied by fewer IFN-γ–producing T cells, and an increased ratio of CD4+Foxp3+ Tregs to CD4+IFN-γ+ or to CD8+IFN-γ+ T cells, respectively, in pancreatic islets. Transgenic T cells showed markedly decreased TCR-mediated effector cell responses such as proliferation and Th1 differentiation. By contrast, the inhibitory effect of transgenic Pep on TCR signaling did not affect the differentiation of Tregs or their suppressive activity. Adoptive transfer experiments showed that transgenic splenocytes exhibited attenuated diabetogenic ability. To examine further the pathogenic features of transgenic T cells, we generated Ptpn22/BDC2.5 doubly transgenic mice and found reduced proliferation and Th1 differentiation in CD4+ T lymphocytes with additional Pep in pancreatic lymph nodes but not in inguinal lymph nodes of NOD/SCID recipients. This finding indicates that transgenic Pep attenuates T cell functions in an islet Ag–driven manner. Taken together, our results demonstrate that Pep overexpression in T cells attenuates autoimmune diabetes in NOD mice by preferentially modulating TCR signaling–mediated functions in diabetogenic T cells but not in Tregs.

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“…c-Cbl −/− mice were provided by J. Chiang (National Cancer Institute, Bethesda, MD). Themis1 −/− (5), Themis1-tg (9), Grb2 +/− (33), TCRz 6Y/6Y (46), and TCRz 6F/6F (46) mice were described previously. The AND and OT-2-TCR transgenic mice were obtained from Taconic Farms.…”

Section: Micementioning

confidence: 99%

Themis1 enhances T cell receptor signaling during thymocyte development by promoting Vav1 activity and Grb2 stability

et al. 2016

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The T cell signaling protein Themis1 is essential for the positive and negative selection of thymocytes in the thymus. Although the developmental defect that results from the loss of Themis1 suggests that it enhances T cell receptor (TCR) signaling, Themis1 also recruits Src homology 2 domain-containing phosphatase-1 (SHP-1) to the vicinity of TCR signaling complexes, suggesting that it has an inhibitory role in TCR signaling. We used TCR signaling reporter mice and quantitative proteomics to explore the role of Themis1 in developing T cells. We found that Themis1 acted mostly as a positive regulator of TCR signaling in vivo when receptors were activated by positively selecting ligands. Proteomic analysis of the Themis1 interactome identified SHP-1, the TCR-associated adaptor protein Grb2, and the guanine nucleotide exchange factor Vav1 as the principal interacting partners of Themis1 in isolated mouse thymocytes. Analysis of TCR signaling in Themis1-deficient and Themis1-overexpressing mouse thymocytes demonstrated that Themis1 promoted Vav1 activity both in vitro and in vivo. The reduced activity of Vav1 and the impaired T cell development in Themis1 −/− mice were due in part to increased degradation of Grb2, which suggests that Themis1 is required to maintain the steady-state abundance of Grb2 in thymocytes. Together, these data suggest that Themis1 acts as a positive regulator of TCR signaling in developing T cells, and identify a mechanism by which Themis1 regulates thymic selection.

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Reduced TCR signaling potential impairs negative selection but does not result in autoimmune disease

Abstract: TCR signal attenuation selectively favors Foxp3 expression and T reg cell lineage commitment.

Cited by 47 publications

References 59 publications

SATB1 Plays a Critical Role in Establishment of Immune Tolerance

SATB1 Plays a Critical Role in Establishment of Immune Tolerance

Different Modulation of Ptpn22 in Effector and Regulatory T Cells Leads to Attenuation of Autoimmune Diabetes in Transgenic Nonobese Diabetic Mice

Themis1 enhances T cell receptor signaling during thymocyte development by promoting Vav1 activity and Grb2 stability

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