Research ArticleTHYMIC SELECTION

The early proximal αβ TCR signalosome specifies thymic selection outcome through a quantitative protein interaction network

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Science Immunology  15 Feb 2019:
Vol. 4, Issue 32, eaal2201
DOI: 10.1126/sciimmunol.aal2201

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Instructional signals for nascent T cells

Signals relayed through the TCR/CD3 complex are critical to determining whether immature T cells in the thymus undergo positive selection, enabling their survival and subsequent export to the periphery, or negative selection leading to death. Neier et al. developed a proteomics-based approach to profile proteins bound to the TCR/CD3 complex that enabled a comparison of differences between signaling associated with thymocyte survival versus death. They observed that the full range of cellular outcomes after thymic selection can be attributed to quantitative differences in a shared core set of biochemical signals. These findings indicate that differences in the affinity of TCRs for peptide-MHC complexes are transduced into downstream signals that are quantitatively variable but qualitatively similar.

Abstract

During αβ T cell development, T cell antigen receptor (TCR) engagement transduces biochemical signals through a protein-protein interaction (PPI) network that dictates dichotomous cell fate decisions. It remains unclear how signal specificity is communicated, instructing either positive selection to advance cell differentiation or death by negative selection. Early signal discrimination might occur by PPI signatures differing qualitatively (customized, unique PPI combinations for each signal), quantitatively (graded amounts of a single PPI series), or kinetically (speed of PPI pathway progression). Using a novel PPI network analysis, we found that early TCR-proximal signals distinguishing positive from negative selection appeared to be primarily quantitative in nature. Furthermore, the signal intensity of this PPI network was used to find an antigen dose that caused a classic negative selection ligand to induce positive selection of conventional αβ T cells, suggesting that the quantity of TCR triggering was sufficient to program selection outcome. Because previous work had suggested that positive selection might involve a qualitatively unique signal through CD3δ, we reexamined the block in positive selection observed in CD3δ0 mice. We found that CD3δ0 thymocytes were inhibited but capable of signaling positive selection, generating low numbers of MHC-dependent αβ T cells that expressed diverse TCR repertoires and participated in immune responses against infection. We conclude that the major role for CD3δ in positive selection is to quantitatively boost the signal for maximal generation of αβ T cells. Together, these data indicate that a quantitative network signaling mechanism through the early proximal TCR signalosome determines thymic selection outcome.

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