T Cell Receptor Cross-Reactivity between Similar Foreign and Self Peptides Influences Naive Cell Population Size and Autoimmunity

Abstract

SUMMARY T cell receptor (TCR) cross-reactivity between major histocompatibility complex II (MHCII)-binding self and foreign peptides could influence the naïve CD4+ T cell repertoire and autoimmunity. We found that nonamer peptides that bind to the same MHCII molecule only need to share five amino acids to cross-react on the same TCR. This property was biologically relevant since systemic expression of a self peptide reduced the size of a naïve cell population specific for a related foreign peptide by deletion of cells with cross-reactive TCRs. Reciprocally, an incompletely deleted naïve T cell population specific for a tissue-restricted self peptide could be triggered by related microbial peptides to cause autoimmunity. Thus, TCR cross-reactivity between similar self and foreign peptides can reduce the size of certain foreign peptide-specific T cell populations, and may allow T cell populations specific for tissue-restricted self peptides to cause autoimmunity after infection.

Calnexin Induces Expansion of Antigen-Specific CD4+ T Cells that Confer Immunity to Fungal Ascomycetes via Conserved Epitopes

“…It is likely that the nonamer core for peptide #1 is VKNPAAHHA (Table 1) . For the class II MHC, I-Ab, P1, 3, 4, 5, 7, 9 make contacts with I-Ab, and P2, 5, 7, and 8 are usually the most important TCR contacts, especially P5 (Nelson et al, 2014). Calnexin from C. immitis and Aspergillus can be detected by VKNPAAHHA:I-Ab-specific T cells because A or V at P4 are permissive for I-Ab binding and these peptides have the same TCR contact amino acids at P2, 5, 7, and 8 as calnexin from B. dermatitidis .…”

“…The size of the pool of naïve precursors specific for calnexin peptide #1 is an average size (Nelson et al, 2014) of 30 cells. Because the size of this precursor pool dictates the ultimate number of Ag-specific T cells in the expanded pool after vaccination (Moon et al, 2007), we sought to expand this pool to boost calnexin vaccine efficacy.…”

T follicular regulatory cells in the regulation of B cell responses

“…Central tolerance is one mechanism that prevents autoimmunity because self-reactive T and B cells are largely deleted. Some self-reactive cells, however, escape into the periphery[6]. In the periphery, the requirement for innate receptor-mediated “stranger/danger” signals for antibody production is another mechanism that prevents autoimmunity [7, 8].…”

Microbiota and Autoimmunity: Exploring New Avenues

“…Novel approaches involving MHC-peptide tetramers in humans (Su et al, 2013) and mice (Nelson et al, 2014) have provided concrete evidence for the existence of T cell receptors (TCR) that cross-react to peptides that the host was not previously exposed to. Synthetic peptides derived from microbes were able to activate cells carrying such TCRs.…”