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Themis releases the brakes on TCR signaling during thymocyte selection by disabling SHP-1

Cellular & Molecular Immunology volume 14, pages 724–726 (2017)Cite this article

In this issue of Nature Immunology, Choi and colleagues1 identify a key function of the T cell-specific protein thymocyte-expressed molecule involved in selection (THEMIS) in T cell development. They demonstrate that the two structural CABIT (cysteine-containing all beta in THEMIS) modules contained in this protein are able to directly bind to the phosphotyrosine-phosphatase (PTP) domain of SHP-1 (Src homology region 2 domain-containing phosphatase-1) and inhibit its phosphatase activity by increasing the susceptibility of its catalytic site to oxidation. By keeping SHP-1 under control, THEMIS enhances the T cell receptor signaling response to low-affinity self-peptides (self-p) presented as a complex with the major histocompatibility complex (MHC) by stromal cells of the thymus. These findings highlight a key role for THEMIS in the positive selection of thymocytes.

T cells originate from hematopoietic stem cells in the bone marrow as lymphoid progenitors, which then migrate to populate the thymus, where they expand to generate a large population of immature thymocytes.2 A series of steps then induces the differentiation of thymocytes to mature T cells.3 These steps are defined by the expression of the co-receptors CD4 and CD8, with thymocytes transiting from the CD4−/CD8− double negative stage to the CD4+/CD8+ double positive (DP) stage and finally to the CD4+ or CD8+ single positive (SP) stage.3 This complex developmental program is regulated by signals triggered by immature or mature forms of the T cell receptor. An interesting paradox is that TCR-driven responses elicit two diametrically opposed outcomes on DP thymocytes, that is, negative selection and subsequent death by apoptosis if they express TCRs that fail to bind or that bind with high affinity to self-p/MHCs on thymic antigen-presenting cells, and positive selection, which allows them to proceed along the differentiation pathway if their TCRs bind with low-affinity to self-p/MHCs.4 Hence, the strength of TCR binding to self-p/MHCs during the selection process controls the intensity and the duration of the TCR-driven signaling response, ultimately leading to the differential activation of downstream signaling pathways and transcriptional responses that dictate cell fate.4, 5 The intriguing question is how the signaling machinery of differentiating thymocytes interprets different TCR signal intensities and durations, responding with distinct gene expression patterns. Thymocytes at the DP stage are more responsive to low-affinity peptides compared with mature T cells, supporting the notion that their TCRs are endowed with a higher sensitivity to self-p/MHCs compared with TCRs that are expressed by mature T cells.6

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References

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  1. Department of Life Sciences, University of Siena, Siena, 53100, Italy

    Laura Patrussi & Cosima T Baldari

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  1. Laura Patrussi
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Correspondence to Laura Patrussi or Cosima T Baldari.

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Patrussi, L., Baldari, C. Themis releases the brakes on TCR signaling during thymocyte selection by disabling SHP-1. Cell Mol Immunol 14, 724–726 (2017). https://doi.org/10.1038/cmi.2017.41

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