TCR Bias and Affinity Define Two Compartments of the CD1b–Glycolipid-Specific T Cell Repertoire

Abstract

Current views emphasize T cell receptor (TCR) diversity as a key feature that differentiates the group 1 (CD1a, CD1b, CD1c) and group 2 (CD1d) CD1 systems. Whereas TCR sequence motifs define CD1d-reactive NKT cells, the available data do not allow a TCR-based organization of the group 1 CD1 repertoire. The observed TCR diversity might result from donor to donor differences in TCR repertoire, as seen for MHC-restricted T cells. Alternatively, diversity might result from differing CD1 isoforms, antigens and methods used to identify TCRs. Using CD1b tetramers to isolate clones recognizing the same glycolipid, we identified a previously unknown pattern of variable (V) gene usage (TRAV17, TRBV4-1) among unrelated human subjects. These TCRs are distinct from those present on NKT cells and germline-encoded mycolyl lipid reactive (GEM) T cells. Instead, they resemble the TCR of LDN5, one of the first known CD1b-reactive clones that was previously thought to illustrate the diversity of the TCR repertoire. Interdonor TCR conservation was observed in vitro and ex vivo, identifying LDN5-like T cells as a distinct T cell type. These data support TCR-based organization of the CD1b repertoire, which consists of at least two compartments that differ in TCR sequence motifs, affinity, and co-receptor expression.

CD1b-restricted GEM T cell responses are modulated byMycobacterium tuberculosismycolic acid meromycolate chains

“…Mycolates comprise a structurally diverse species of Mtb cell wall lipids which can activate CD1b-restricted human T cells (9,26), including GEM T cells (9,26). However, antigenic determinants of mycobacterial mycolates for CD1b-restricted T cells have not been fully defined.…”

“…However, antigenic determinants of mycobacterial mycolates for CD1b-restricted T cells have not been fully defined. To investigate this, we generated human J.RT3.T3-5 and NFAT-GLuc Jurkat T cells stably expressing the mycolate-specific TCRs, GEM clone 1 (GEM1), GEM clone 18 (GEM18), and LDN5 (9,26). Jurkat T cells expressing TCR were activated by CD1b in the presence of mycolate, whereas no activation occurred in the absence of either the TCR, CD1b or mycolate ( Fig.…”

“…Knowledge of the CD1b-mycolate specific T cell compartment has until recently been based on a few isolated clones that may not accurately represent the T cell repertoire in vivo (9,26). More recently, CD1b-tetramers have been developed to efficiently capture GMM-specific T cells (9).…”

Human autoreactive T cells recognize CD1b and phospholipids

“…Prior work using human T-cell clones (3)(4)(5)(6)(7) and the recently developed human CD1a, CD1b, and CD1c tetramers (8)(9)(10) has demonstrated the existence of mycobacteria-reactive T cells, including polyclonal T cells with stereotyped T-cell receptors (TCRs), known as germline-encoded mycolyl lipid-reactive T cells (11) and LDN5-like T cells (12). At this time, nearly all known foreign antigens presented by CD1b, including mycolic acid, glucose monomycolate, glycerol monomycolate, and sulfoglycolipids, are selectively synthesized by Mycobacterium tuberculosis and related mycobacterial species.…”

“…To address the breadth of pathogens recognized by CD1b-mediated T cells, we studied human T-cell responses to pathogenic Salmonella, Staphylococcus, and Brucella species. CD1b tetramers have recently been proven to markedly enhance the rate of detection and recovery of CD1b-reactive T cells (8,11,12). However, tetramers are not usually used for antigen discovery because they require that homogenous antigen preparations be loaded onto MHC or CD1 proteins.…”