Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 37, Issue 3, Pages 602-612Publisher
WILEY
DOI: 10.1002/eji.200636787
Keywords
autoimmunity; multispecific response; TCR
Categories
Funding
- NIAID NIH HHS [P01AI39671] Funding Source: Medline
- NINDS NIH HHS [NS24247] Funding Source: Medline
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The paradox of autoreactivity to self-peptides in physiological as opposed to pathological immune responses is not well understood. Here, we directly examined the human T cell response to endogenous self-peptides in a series of healthy subjects. CFSE-labeled T cells were stimulated with unmanipulated antigen-presenting cells containing endogenous self-antigen, and the resulting CD4(+) populations entering into cell cycle (CFSElow) or non-proliferating CD4(+) cells (CFSEhigh) were single-cell sorted, cloned and screened against a panel of self-antigens and microbial recall antigens to interrogate their antigen reactivity. The percentage of CD4(+) T cells entering cell cycle in response to self-peptide/MHC was calculated to be 0.04%, and entry into cell cycle was dependent upon CD28 costimulation. Clones derived from CFSElow T cells exhibited significantly greater cross-reactivity to multiple antigens than CFSEhigh clones or other CD4(+) clones generated after microbial antigen stimulation. Sequencing the TCRP chains indicated that CFSElow clones were indeed clonal. These data demonstrate that T cell clones generated on stimulation by endogenous self-peptides exhibit a high degree of multispecificity, and we speculate that their multispecificity is based upon recognition of shared-backbone MHC determinants.
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