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Dyslipidemia, or altered blood lipid content, is a risk factor for developing cardiovascular disease. Furthermore, several autoimmune diseases, including systemic lupus erythematosus, psoriasis, diabetes, and rheumatoid arthritis, are correlated highly with dyslipidemia. One common thread between both autoimmune diseases and altered lipid levels is the presence of inflammation, suggesting that the immune system might act as the link between these related pathologies. Deciphering the role of innate and adaptive immune responses in autoimmune diseases and, more recently, obesity-related inflammation, have been active areas of research. The broad picture suggests that antigen-presenting molecules, which present self-peptides to autoreactive T cells, can result in either aggravation or amelioration of inflammation. However, very little is known about the role of self-lipid reactive T cells in dyslipidemia-associated autoimmune events. Given that a range of autoimmune diseases are linked to aberrant lipid profiles and a majority of lipid-specific T cells are reactive to self-antigens, it is important to examine the role of these T cells in dyslipidemia-related autoimmune ailments and determine if dysregulation of these T cells can be drivers of autoimmune conditions. CD1 molecules present lipids to T cells and are divided into two groups based on sequence homology. To date, most of the information available on lipid-reactive T cells comes from the study of group 2 CD1d-restricted natural killer T (NKT) cells while T cells reactive to group 1 CD1 molecules remain understudied, despite their higher abundance in humans compared to NKT cells. This review evaluates the mechanisms by which CD1-reactive, self-lipid specific T cells contribute to dyslipidemia-associated autoimmune disease progression or amelioration by examining available literature on NKT cells and highlighting recent progress made on the study of group 1 CD1-restricted T cells. [ABSTRACT FROM AUTHOR]

A large proportion of human T cells are autoreactive to group 1 CD1 proteins, which include CD1a, CD1b, and CD1c. However, the physiological role of the CD1 proteins remains poorly defined. Here, we have generated a double-transgenic mouse model that expresses human CD1b and CD1c molecules (hCD1Tg) as well as a CD1b-autoreactive TCR (HJ1Tg) in the ApoE-deficient background (hCD1Tg HJ1Tg Apoe-/- mice) to determine the role of CD1-autoreactive T cells in hyperlipidemia-associated inflammatory diseases. We found that hCD1Tg HJ1Tg Apoe-/- mice spontaneously developed psoriasiform skin inflammation characterized by T cell and neutrophil infiltration and a Th17-biased cytokine response. Anti-IL-17A treatment ameliorated skin inflammation in vivo. Additionally, phospholipids and cholesterol preferentially accumulated in diseased skin and these autoantigens directly activated CD1b-autoreactive HJ1 T cells. Furthermore, hyperlipidemic serum enhanced IL-6 secretion by CD1b+ DCs and increased IL-17A production by HJ1 T cells. In psoriatic patients, the frequency of CD1b-autoreactive T cells was increased compared with that in healthy controls. Thus, this study has demonstrated the pathogenic role of CD1b-autoreactive T cells under hyperlipidemic conditions in a mouse model of spontaneous skin inflammation. As a large proportion of psoriatic patients are dyslipidemic, this finding is of clinical significance and indicates that self-lipid-reactive T cells might serve as a possible link between hyperlipidemia and psoriasis. [ABSTRACT FROM AUTHOR]

Adoptive immunotherapy for cancer treatment is an emerging field of study. Till now, several tumor-derived, peptide-specific T cell responses have been harnessed for treating cancers. However, the contribution of lipid-specific T cells in tumor immunity has been understudied. CD1 molecules, which present self- and foreign lipid antigens to T cells, are divided into group 1 (CD1a, CD1b, and CD1c) and group 2 (CD1d). Although the role of CD1d-restricted natural killer T cells (NKT) in several tumor models has been well established, the contribution of group 1 CD1-restricted T cells in tumor immunity remains obscure due to the lack of group 1 CD1 expression in mice. In this study, we used a double transgenic mouse model expressing human group 1 CD1 molecules (hCD1Tg) and a CD1b-restricted, self-lipid reactive T cell receptor (HJ1Tg) to study the potential role of group 1 CD1-restricted autoreactive T cells in antitumor response. We found that HJ1 T cells recognized phospholipids and responded more potently to lipid extracted from tumor cells than the equivalent amount of lipids extracted from normal cells. Additionally, the autoreactivity of HJ1 T cells was enhanced upon treatment with various intracellular toll-like receptor (TLR) agonists, including CpG oligodeoxynucleotides (ODN), R848, and poly (I:C). Interestingly, the adoptive transfer of HJ1 T cells conferred protection against the CD1b-transfected murine T cell lymphoma (RMA-S/CD1b) and CpG ODN enhanced the antitumor effect. Thus, this study, for the first time, demonstrates the antitumor potential of CD1b-autoreactive T cells and their potential use in adoptive immunotherapy. [ABSTRACT FROM PUBLISHER]

Group 1 CD1 molecules, CD1a, CD1b and CD1c, present lipid antigens from Mycobacterium tuberculosis (Mtb) to T cells. Mtb lipid-specific group 1 CD1-restricted T cells have been detected in Mtb-infected individuals. However, their role in protective immunity against Mtb remains unclear due to the absence of group 1 CD1 expression in mice. To overcome the challenge, we generated mice that expressed human group 1 CD1 molecules (hCD1Tg) and a CD1b-restricted, mycolic-acid specific TCR (DN1Tg). Using DN1Tg/hCD1Tg mice, we found that activation of DN1 T cells was initiated in the mediastinal lymph nodes and showed faster kinetics compared to Mtb Ag85B-specific CD4+ T cells after aerosol infection with Mtb. Additionally, activated DN1 T cells exhibited polyfunctional characteristics, accumulated in lung granulomas, and protected against Mtb infection. Therefore, our findings highlight the vaccination potential of targeting group 1 CD1-restricted lipid-specific T cells against Mtb infection. [ABSTRACT FROM AUTHOR]

For many solid malignancies, lymph node (LN) involvement represents a harbinger of distant metastatic disease and, therefore, an important prognostic factor. Beyond its utility as a biomarker, whether and how LN metastasis plays an active role in shaping distant metastasis remains an open question. Here, we develop a syngeneic melanoma mouse model of LN metastasis to investigate how tumors spread to LNs and whether LN colonization influences metastasis to distant tissues. We show that an epigenetically instilled tumor-intrinsic interferon response program confers enhanced LN metastatic potential by enabling the evasion of NK cells and promoting LN colonization. LN metastases resist T cell-mediated cytotoxicity, induce antigen-specific regulatory T cells, and generate tumor-specific immune tolerance that subsequently facilitates distant tumor colonization. These effects extend to human cancers and other murine cancer models, implicating a conserved systemic mechanism by which malignancies spread to distant organs. [Display omitted] • Chronic IFN signaling induces epigenetic rewiring of tumor cells and immune escape • MHC-I and PD-L1 expression enables the evasion of NK cells and suppression of T cells • LN colonization induces broad alterations in the local immune repertoire • LN metastases induce antigen-specific Tregs that promote distant metastasis Facilitated by a tumor-intrinsic interferon response program, lymph node colonization promotes metastasis to distant organs by inducing broad alterations in tumor immunity and generating tumor-specific immune tolerance. [ABSTRACT FROM AUTHOR]