Multispecific responses by T cells expanded by endogenous self-peptide/MHC complexes

Eur J Immunol. 2007 Mar;37(3):602-12. doi: 10.1002/eji.200636787.


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 (CFSE(low)) or non-proliferating CD4+ cells (CFSE(high)) 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 CFSE(low) T cells exhibited significantly greater cross-reactivity to multiple antigens than CFSE(high) clones or other CD4+ clones generated after microbial antigen stimulation. Sequencing the TCRbeta chains indicated that CFSE(low) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoantigens / immunology*
  • Clone Cells
  • Epitopes, T-Lymphocyte / immunology*
  • HLA Antigens / immunology*
  • HLA Antigens / metabolism
  • Humans
  • Lymphocyte Activation / immunology
  • Major Histocompatibility Complex*
  • Mice
  • Peptides / immunology*
  • Peptides / metabolism
  • Protein Binding / immunology
  • Receptors, Antigen, T-Cell / metabolism
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism


  • Autoantigens
  • Epitopes, T-Lymphocyte
  • HLA Antigens
  • Peptides
  • Receptors, Antigen, T-Cell