Naive T cell clonal size is influenced by breadth of self-antigen cross-reactivity

While both B cells and T cells developed to detect foreign antigens, the basic mechanisms behind this process for these two population are fundamentally different. Unlike B cells, T cells recognize foreign epitope presented on MHC plate. The size of epitope detected by T cell receptor (TCR) is usually 9 amino acid long. Such constraint imposed on T cell receptor creates potential for cross-reactivity leading to autoimmunity.

This new study in journal Immunity went further to show that out of 9 amino acids that make up TCR recognition field, changes in only 5 amino acids have the major impact on TCR recognition and T cell population size.

First, the authors, led by Marc Jenkins at the University of Minnesota, Center for Immunology, have determined the population size of mouse naive CD4 T cells specific for a dozen of foreign antigens. Immunization with these specific antigens showed that magnitude of CD4 T cell response correlated with the number of antigen-specific naive T cells.

Next the authors synthesized 11 variant peptides for each 13 peptide examined by substituting each amino acid with alanine at positions P1-P10 ( TCR recognition field). Parental peptide immunized mice were then tested for T cell reactivity to variant peptides in ELISpot assay. The authors found that changes in amino acids in Position 2, 5, 7, 8 could reduce T cell responsiveness by >90%.

To understand how TCR cross-reactivity could affect the variant peptide, 2W109-specific T cell population size and its responsiveness to 2W109, the authors have used act-2W mice that express 2W epitope in the thymus. 2W differs from 2W109 at position 1, 4, 6, 9. Double tetramer staining revealed that compared to B6 mice, in act-2W mice, T cells cross-reactive for both 2W and 2W109 peptide were significantly reduced (B6 mice ~ 180 T cells, act-2W mice ~ 40 T cells). 

Additional experiments indicated that 2W109-specific T cells, that remained in act-2W mice after negative selection, developed heightened sensitivity to amino acid substitution across all 9-mer, including anchor amino acids, implying increased dependency on peptide conformation for TCR recognition.

Indeed, re-analysis of parental foreign peptide-specific T cells responsiveness to variant peptides revealed that increased sensitivity to anchor amino acids substitution correlated with reduction of clonal size, suggesting negative selection against potential self-epitopes.

This study suggests that clonal size of naive T cell specific to any given foreign antigen is determined by the number of self-antigen it happens to cross-react. It addition, these results indicate that TCR cross-reactive for self-epitopes becomes heavily dependent on peptide conformation and may have low affinity for foreign antigens.  

This results, while quite complex, provided a guiding principle how to study T cell responses or how to design T cell specific vaccines.   

Please, leave your comments below. Let me know what do you think about this paper or my analysis.

David Usharauli