CD1a-autoreactive T cells are a normal component of the human αβ T cell repertoire

Jong, Annemieke de; Peña‐Cruz, Victor; Cheng, Tan-Yun; Clark, Rachael A.; Rhijn, Ildiko Van; Moody, D. Branch

doi:10.1038/ni.1956

Cited by 220 publications

(318 citation statements)

References 59 publications

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“…Interestingly, the Ags recognized by gd T cells include nonpeptide compounds associated with MHC-like molecules such as CD1 (50,51). In humans, it was recently shown that a particular population of CD4 + T cells homed to skin, where they produced IL-22 in response to CD1a on Langerhans cells (52). It is tempting to speculate that imiquimod activation of Langerhans cells similarly allows for presentation of nonpeptide Ags via MHC-like molecules to both gd T cells or unconventional CD4 + or CD8 + T cells.…”

Section: Discussionmentioning

confidence: 99%

IL-22 Is Required for Imiquimod-Induced Psoriasiform Skin Inflammation in Mice

Belle

Heusch

Lemaire

et al. 2012

The Journal of Immunology

254

234

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Psoriasis is a common chronic autoimmune skin disease of unknown cause that involves dysregulated interplay between immune cells and keratinocytes. IL-22 is a cytokine produced by the TH1, TH17, and TH22 subsets that are functionally implicated in the psoriatic pathology. We assessed the role of IL-22 in a mouse model where psoriasiform skin inflammation is triggered by topical application of the TLR7/8 agonist imiquimod. At the macroscopic level, scaly skin lesions induced by daily applications of imiquimod in wild-type mice were almost totally absent in IL-22–deficient mice or in mice treated with a blocking anti–IL-22 Ab. At the microscopic level, IL-22–deficient mice showed a dramatic decrease in the development of pustules and a partial decrease in acanthosis. At the molecular level, the absence or inhibition of IL-22 strongly decreased the expression of chemotactic factors such as CCL3 and CXCL3 and of biomarkers such as S100A8, S100A7, and keratin 14, which reflect the antimicrobial and hyperproliferative responses of keratinocytes. IL-22 also played a major role in neutrophil infiltration after imiquimod treatment. IL-23 was required for IL-22 production, and γδ TCR lymphocytes represented the major source of IL-22 in lymph nodes from imiquimod-treated mice. However, T cells were not absolutely required for IL-22 production because imiquimod-induced IL-22 expression in the skin is still preserved in Rag2−/− mice. Taken together, our data show that IL-22 is required for psoriasis-like lesions in the mouse imiquimod model and is produced by both T cells and innate immune cells.

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Section: Discussionmentioning

confidence: 99%

IL-22 Is Required for Imiquimod-Induced Psoriasiform Skin Inflammation in Mice

Belle

Heusch

Lemaire

et al. 2012

The Journal of Immunology

254

234

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“…Zippered CD1 proteins were generated by stabilizing β2m and the heavy chain with C-terminal zipper sequences. The linked and zippered CD1 proteins together with MHC class I controls HLA-B2705 and MamuA01 were expressed in K562 (34) and HEK293 (4, 5), respectively. The secreted proteins were purified as described (24).…”

Section: Methodsmentioning

confidence: 99%

Discovery of deoxyceramides and diacylglycerols as CD1b scaffold lipids among diverse groove-blocking lipids of the human CD1 system

Huang

Cheng

Young

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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102

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Unlike the dominant role of one class II invariant chain peptide (CLIP) in blocking MHC class II, comparative lipidomics analysis shows that human cluster of differentiation (CD) proteins CD1a, CD1b, CD1c, and CD1d bind lipids corresponding to hundreds of diverse accurate mass retention time values. Although most ions were observed in association with several CD1 proteins, ligands binding selectively to one CD1 isoform allowed the study of how differing antigenbinding grooves influence lipid capture. Although the CD1b groove is distinguished by its unusually large volume (2,200 Å 3 ) and the T′ tunnel, the average mass of compounds eluted from CD1b was similar to that of lipids from CD1 proteins with smaller grooves. Elution of small ligands from the large CD1b groove might be explained if two small lipids bind simultaneously in the groove. Crystal structures indicate that all CD1 proteins can capture one antigen with its hydrophilic head group exposed for T-cell recognition, but CD1b structures show scaffold lipids seated below the antigen. We found that ligands selectively associated with CD1b lacked the hydrophilic head group that is generally needed for antigen recognition but interferes with scaffold function. Furthermore, we identified the scaffolds as deoxyceramides and diacylglycerols and directly demonstrate a function in augmenting presentation of a small glycolipid antigen to T cells. Thus, unlike MHC class II, CD1 proteins capture highly diverse ligands in the secretory pathway. CD1b has a mechanism for presenting either two small or one large lipid, allowing presentation of antigens with an unusually broad range of chain lengths.antigen presentation | Mycobacterium tuberculosis | cluster of differentiation 1

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“…+ DCs, it might even mediate the presentation of lipids onto nonclassical MHC class I and the priming of CD1a-restricted Th22, as seen in patients with psoriasis (14,43).…”

Section: Cd1cmentioning

confidence: 99%

“…In contrast, LCs enhance cellular immunity by inducing Th2 differentiation of naive CD4 + T cells and via priming and cross-priming of naive CD8 + T cells (5,9,11). Recently, human LCs were also shown to be responsible for directing IL-17-and IL-22-mediated responses (12)(13)(14)(15), two responses indicative of inflammatory autoimmune skin diseases, such as psoriasis.…”

Section: Introductionmentioning

confidence: 99%