The strength with which complexes of self peptide and major histocompatibility complex (MHC) proteins are recognized by the T cell antigen receptor (TCR) dictates the homeostasis of naive CD8+ T cells, but its effect on reactivity to foreign antigens is controversial. As expression of the negative regulator CD5 correlates with self-recognition, we studied CD5lo and CD5hinaive CD8+ T cells. Gene-expression characteristics suggested CD5 hi cells were better poised for reactivity and differentiation than were CD5lo cells, and we found that the CD5hi pool also exhibited more efficient clonal recruitment and expansion, as well as enhanced reactivity to inflammatory cues, during the recognition of foreign antigen. However, the recognition of complexes of foreign peptide and MHC was similar for both subsets. Thus, CD8 + T cells with higher self-reactivity dominate the immune response to foreign antigens, with implications for T cell repertoire diversity and autoimmunity.
Bibliographical noteFunding Information:
We thank D. Masopust (University of Minnesota) for Il15−/− mice, P14 mice and LCMV Armstrong strain; L. Cauley (University of Connecticut) for F5 mice deficient in recombination-activating gene 1; J. Zhu (National Institute of Allergy and Infectious Diseases) for T-bet–ZsGreen reporter mice; J. Harty (University of Iowa) for L. monocytogenes strain ∆actA (DP-L1942) and OVA-expressing L. monocytogenes ∆actA; R. Kedl (National Jewish Medical Research Center) for LM-B8R (virulent and ∆actA); M. Prlic and M. Bevan (University of Washington) and J. Harty (University of Iowa) for Flt3L-expressing B16 cells; R. Kroczek (Robert Koch-Institute) for the conjugated monoclonal antibody MTAC-2; the University of Minnesota Flow Core personnel for flow-cytometry support and cell sorting; M. Jenkins and M. Mescher for critical review of the manuscript; G. Stritesky for insight on the analysis of Nur77 mice; J. Ding and S. Peery for technical assistance with mice; and members of the Jamequist laboratory for discussions. Supported by the US National Institutes of Health (R37 AI-38903 to S.C.J.; P30 CA77598, with the Biostatistics and Bioinformatics Core shared resource of the Masonic Cancer Center, University of Minnesota; UL1TR000114 from the National Center for Advancing Translational Sciences) and the Irvington Institute Fellowship Program of the Cancer Research Institute (R.B.F.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the US National Institutes of Health.