Fig. 5. Potential mechanisms of how basal self-reactivity contributes to T cell sensitivity to pathogens.

(A) High levels of self-reactivity increase the abundances of negative regulators of TCR signaling, including Shp-1, Shp-2, Cbl-b, CD5, Csk, Ptpn22, and CD45. CD45 dephosphorylates Lck and the CD3ζ chain to inhibit downstream signaling in the absence of antigen stimulation. The Lck kinase domain contains an activating tyrosine, Tyr³⁹⁴ and an inhibitory tyrosine, Tyr⁵⁰⁵. When Tyr³⁹⁴ is solely phosphorylated, Lck is fully active, whereas phosphorylation of Tyr⁵⁰⁵ inhibits Lck activity. By dephosphorylating both residues of Lck and Cd3ζ, CD45 limits, but does not abolish, Lck kinase function and counterbalances CD3ζ-chain phosphorylation. Csk is recruited to PAG and further limits Lck kinase activity by phosphorylating Lck Tyr⁵⁰⁵. Ptpn22 is a cytosolic phosphatase that once recruited to the plasma membrane can also inhibit Lck and Zap-70 activities. Shp-1 is recruited to the plasma membrane by different receptors, including CD5, and it inhibits TCR signaling by dephosphorylating Lck, Zap-70, and CD3ζ. Themis associates with LAT through Grb-2 and can inhibit SHP-1. c-Cbl and Cbl-b are E3 ubiquitin ligases that target ZAP-70 and CD3ζ for degradation and interrupt ZAP-70–CD3ζ interactions, respectively. CD5 is a membrane receptor that, when phosphorylated at cytosolic tyrosines by Lck, can recruit the inhibitory proteins c-Cbl, Cbl-b, UBASH3A, and Csk and bring them to the TCR complex. (B) Basal levels of self-reactivity influence TCR sensitivity through expression of negative regulators of TCR signals (Shp-1, Shp-2, Cbl, CD5, and CD45), which limit TCR signaling; phosphorylation of Zap-70, ERK, PLCγ1, and expression of LAT and IκB/NF-κB. Alterations further bias the T cell response to be receptive to cytokines, including IL-2 and type-1 IFN. The graph is for visualization purposes and relative differences in expression are not to scale.