Human autoreactive T cells recognize CD1b and phospholipids

Abstract

In contrast with the common detection of T cells that recognize MHC, CD1a, CD1c, or CD1d proteins, CD1b autoreactive T cells have been difficult to isolate in humans. Here we report the development of polyvalent complexes of CD1b proteins and carbohydrate backbones (dextramers) and their use in identifying CD1b autoreactive T cells from human donors. Activation is mediated by αβ T-cell receptors (TCRs) binding to CD1b-phospholipid complexes, which is sufficient to activate autoreactive responses to CD1b-expressing cells. Using mass spectrometry and T-cell responses to scan through the major classes of phospholipids, we identified phosphatidylglycerol (PG) as the immunodominant lipid antigen. T cells did not discriminate the chemical differences that distinguish mammalian PG from bacterial PG. Whereas most models of T-cell recognition emphasize TCR discrimination of differing self and foreign structures, CD1b autoreactive T cells recognize lipids with dual self and foreign origin. PG is rare in the cellular membranes that carry CD1b proteins. However, bacteria and mitochondria are rich in PG, so these data point to a more general mechanism of immune detection of infection- or stress-associated lipids.

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

“…Recent studies that identified lipid autoantigens in vitro pointed to candidate self-lipids that might function in this in vivo disease, including cholesterol (31), fatty acids (17), and membrane phospholipids (19,45). To identify self-lipids presented by CD1b to HJ1 T cells, CD1b plate-bound assays were performed.…”

“…A recent study also demonstrated that CD1a-restricted T cells responded to neolipid antigens generated by phospholipase A 2 activity in psoriasis patients (30). CD1b-autoreactive T cells can recognize phospholipids (17,19), and a higher frequency of sulfatide and monosialotetrahexosylganglioside-specific (GM1-specific) T cells was detected in multiple sclerosis patients compared with normal controls (26). Moreover, CD1c-restricted T cells specific for cholesteryl esters have recently been identified (31).…”

“…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.…”

CD1b-autoreactive T cells recognize phospholipid antigens and contribute to antitumor immunity against a CD1b+T cell lymphoma

“…29 In addition, recent studies have shown that CD1a-restricted human T cell clones recognize skin-derived apolar oils and phospholipids; autoreactive CD1b-restricted human T cell clones recognize a range of phospholipids, whereas CD1c-reactive clones can bind cholesterol and its esters. [31][32][33] Considering that these lipids accumulate in most tumors, it is imperative to explore the role of autoreactive group 1 CD1-restricted T cells in tumor immunity. This would shed light on the potential use of these T cells in cancer immunotherapy.…”

Phospholipid signals of microbial infection for the human immune system

“…Interestingly, some self-reactive T cells also display cross-reactivity for microbial antigens (Table 1). In PNAS, Van Rhijn et al define the cross-reacting bacterial and self-antigens of a group of T lymphocytes that respond to antigens bound to or presented by CD1b (1). Their findings suggest one mechanism whereby dangerous, CD1-mediated self-reactivity by T cells might be controlled, and the authors provide a hypothesis for why cross-reactive recognition of the antigens they define might be useful.…”