Self-recognition promotes the foreign antigen sensitivity of naive T lymphocytes

Abstract

Major histocompatibility complex (MHC) class I and II molecules are highly polymorphic proteins that bind and present foreign peptides to the clonally distributed αβ receptors (TCR) of T lymphocytes. As a population, the immature T lymphocytes generated in the thymus express a very diverse set of TCR specificities. A process of positive selection filters this broad repertoire to optimize peripheral T cells for antigen recognition in the context of available MHC products. Only those precursor T cells whose TCRs generate an adequate but not excessive signalling response to self-peptides bound to the expressed MHC proteins undergo successful maturation1. Here we show that post-thymic self-recognition facilitates the antigen reactivity of mature T cells. Both experimental and physiological interruption of T-cell contact with self-peptide MHC ligands leads to a rapid decline in signalling and response sensitivity to foreign stimuli. Because the adaptive immune system must be recruited early in an infectious process when antigen is limiting2, these findings suggest that positive selection ensures predictable T-cell recognition of available self-ligands, which in turn promotes efficient responses to pathogens.

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Figure 1: Acute loss of TCR ζ phosphorylation and antigen sensitivity by cultured naive T cells.
Figure 2: Marked decline in TCR signalling and sensitivity to foreign antigen among naive CD4+ T cells deprived of self-MHC class II recognition in vivo.
Figure 3: Peripheral blood CD4+ T cells lacking MHC class II contact have lower TCR ζ phosphorylation and reduced antigen sensitivity compared with lymph node cells from the same animals.
Figure 4: Naive CD4+ T cells show polarized TCR distributions that are maintained by contact with self-MHC class II molecules.

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Acknowledgements

We thank A. Fox for technical support, O. Schwartz for assistance with microscopy and image preparation, S. Stoll for assistance with mice, A. Iwasaki and B. Kelsall for reagents, and the members of the Germain laboratory for discussion.

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Correspondence to Ronald N. Germain.

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The authors declare that they have no competing financial interests.

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Stefanová, I., Dorfman, J. & Germain, R. Self-recognition promotes the foreign antigen sensitivity of naive T lymphocytes. Nature 420, 429–434 (2002). https://doi.org/10.1038/nature01146

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