High‐frequency and adaptive‐like dynamics of human CD1 self‐reactive T cells

Abstract

CD1 molecules present lipid antigens to T cells. An intriguing subset of human T cells recognize CD1-expressing cells without deliberately added lipids. Frequency, subset distribution, clonal composition, naïve-to-memory dynamic transition of these CD1 selfreactive T cells remain largely unknown. By screening libraries of T-cell clones, generated from CD4 1 or CD4 À CD8 À double negative (DN) T cells sorted from the same donors, and by limiting dilution analysis, we find that the frequency of CD1 self-reactive T cells is unexpectedly high in both T-cell subsets, in the range of 1/10-1/300 circulating T cells. These T cells predominantly recognize CD1a and CD1c and express diverse TCRs. Frequency comparisons of T-cell clones from sorted naïve and memory compartments of umbilical cord and adult blood show that CD1 self-reactive T cells are naïve at birth and undergo an age-dependent increase in the memory compartment, suggesting a naïve/ memory adaptive-like population dynamics. CD1 self-reactive clones exhibit mostly Th1 and Th0 functional activities, depending on the subset and on the CD1 isotype restriction. These findings unveil the unanticipated relevance of self-lipid T-cell response in humans and clarify the basic parameters of the lipid-specific T-cell physiology. IntroductionConventional TCR-a/b 1 T lymphocytes recognize peptides presented by MHC molecules and are key players in the adaptive immune response. Thymic selection maximizes the generation of conventional mature T-cell repertoires specific for foreign Ags while minimizing autoreactivity [1]. A key feature of the adaptive immune response is that newly generated conventional T cells are naïve and acquire an effector/memory phenotype upon Ag encounter [2].There exists also an unconventional population of TCR-a/b 1 T lymphocytes that are restricted for CD1 molecules and recognize self-and microbial lipid antigens [3]. CD1 are non-polymorphic MHC class I-like molecules classified into three groups based on the sequence homology: group 1 comprises CD1a, CD1b and CD1c; group 2 CD1d; group 3 CD1e [4]. The best characterized CD1-restricted T cells are the CD1d-restricted invariant Natural Killer à These authors contributed equally to this work. 602Frontline T (iNKT) cells that express, in humans, an invariant Va24-Ja18 TCR paired with Vb11, together with NK-cell receptors [5][6][7]. iNKT cells can be unequivocally identify through their peculiar TCR: they are overly autoreactive, display an innate-like (constitutive) effector/ memory phenotype already at birth [8], unlike conventional T cells, and are divided in two main and functionally distinct CD4 1 and CD4 À CD8 À double negative (DN) subsets [9,10].A second type of CD1-restricted T lymphocytes does not express the invariant TCR and is mainly restricted for group 1 CD1 [3]. Because of the lack of specific markers, this T-cell type has been investigated using sporadically isolated T-cell clones, which provided fundamental hints on the microbial lipids and lipopeptides Ags recognized by these T cells...

Fine tuning by human CD1e of lipid-specific immune responses

“…Human CD1d-restricted type 1 and type 2 NKT, CD1b-restricted and CD1c-restricted T-cell clones, and mouse iNKT hybridomas were derived as described (21)(22)(23) and maintained according to standard procedures. Human monocytic THP-1 and C1R B cells were transfected with human CD1B, CD1C, and CD1D cDNAs alone or in combination with human CD1E cDNA, using the BCMGS-Neo and BCMGS-Hygro vectors (4).…”

CD1b-autoreactive T cells contribute to hyperlipidemia-induced skin inflammation in mice

“…While the involvement of peptide-reactive T cells has been well defined (12)(13)(14)(15), the role of lipid-reactive T cells in psoriasis remains largely unknown. Since psoriasis and cardiovascular disease are correlated with hyperlipidemia and recent studies have identified CD1-restricted self-lipid-reactive T cells in the blood or skin of humans (16)(17)(18)(19), we developed a new mouse model for the study of human CD1-restricted T cell responses to self-lipids in vivo.…”

MiR-381-3p Regulates the Antigen-Presenting Capability of Dendritic Cells and Represses Antituberculosis Cellular Immune Responses by Targeting CD1c

“…de Lalla et al (30) found that CD1c-reactive T cells are unexpectedly high to 66% of self-reactive T cell clones screened in circulating T cells. Due to the large amount of CD1c-restricted T cells in PBMCs, the repression of CD1c expression will consequently compromise T cell activity.…”