Abstract
Since initial reports, more than 25 years ago, that T cells recognize lipids in the context on non-polymorphic CD1 molecules, our understanding of antigen presentation to non-peptide-specific T cell populations has deepened. It is now clear that αβ T cells bearing semi-invariant T cell receptor, as well as subsets of γδ T cells, recognize a variety of self and non-self lipids and contribute to shaping immune responses via cross talk with dendritic cells and B cells. Furthermore, it has been demonstrated that small molecules derived from the microbial riboflavin biosynthetic pathway (vitamin B2) bind monomorphic MR1 molecules and activate mucosal-associated invariant T cells, another population of semi-invariant T cells. Novel insights in the biological relevance of non-peptide-specific T cells have emerged with the development of tetrameric CD1 and MR1 molecules, which has allowed accurate enumeration and functional analysis of CD1- and MR1-restricted T cells in humans and discovery of novel populations of semi-invariant T cells. The phenotype and function of non-peptide-specific T cells will be discussed in the context of the known distribution of CD1 and MR1 molecules by different subsets of antigen-presenting cells at steady state and following infection. Concurrent modulation of CD1 transcription and lipid biosynthetic pathways upon TLR stimulation, coupled with efficient lipid antigen processing, result in the increased cell surface expression of antigenic CD1–lipid complexes. Similarly, MR1 expression is almost undetectable in resting APC and it is upregulated following bacterial infection, likely due to stabilization of MR1 molecules by microbial antigens. The tight regulation of CD1 and MR1 expression at steady state and during infection may represent an important mechanism to limit autoreactivity, while promoting T cell responses to foreign antigens.
Highlights
Earlier studies in the 1990s demonstrated that the antigen recognition potential of T lymphocytes is not limited to peptides presented by MHC class I and class II molecules [1, 2]
While comprehensive reviews on CD1 and MR1 antigen-presenting systems have been recently published [12,13,14,15], we will focus on recent findings that have advanced our understanding of the role of CD1- and MR1restricted T cells, known as non-conventional T cells or innatelike cells, as they straddle between innate and adaptive immunity
We refer the reader to recent reviews for a comprehensive discussion of NKT cell biology and CD1d antigen presentation [12, 14, 69,70,71], while here we highlight the role of microbiota in modulating iNKT cell reactivity and we summarize results revealing a previously unknown heterogeneity of the human NKT cell family (Figure 1)
Summary
Earlier studies in the 1990s demonstrated that the antigen recognition potential of T lymphocytes is not limited to peptides presented by MHC class I and class II molecules [1, 2]. To further characterize the pool of CD1a-autoreactive T cells, Moody, and co-workers have recently designed an experimental system based on CD1-expressing human myelogenous leukemia cells (K562 cells), with low or absent expression of MHC molecules in order to limit allo-reactivity These studies have demonstrated that polyclonal CD1a reactive T cells are present at high frequency in the peripheral blood of healthy individuals [0.02–0.4% of memory T cells [35, 36]]. CD1a molecules were found to stimulate T cell clones when loaded with oily antigens lacking carbohydrate or charged head groups [such as triacylglyceride (TAG), squalene, and wax esters], while lipids with hydrophilic head groups inhibited CD1a-restricted T cell autoreactivity [38] These results, which suggested a unique mode of MAIT cells (reactive to Vitamin B2 derivatives). - iNKT cells - γδ T cells - type II NKT cells (reactive to self and microbial lipids)
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