Lipid-reactive T cells are a heterogeneous population of T lymphocytes with unique specificities for glycolipid and lipid molecules presented in the context of major histocompatibility complex (MHC) class Ib molecules belonging to the CD1 family. They may recognize microbially encoded or synthetic lipids directly through their CD1-restricted T cell receptors (TCRs) or microbial components other than lipids including pathogen-associated molecular patterns (PAMPs) and bacterial superantigens. Once activated, lipid-reactive T cells participate as early effectors and/or regulators of immune responses. Immunoregulatory cytokines produced in copious amounts by these cells target a wide range of downstream effector cells and help shape the ensuing immune responses. The first CD1 molecule appeared around 300 million years ago, and has since diversified tremendously. Mammals comprise various numbers and isoforms of CD1 molecules, suggesting that lipid presentation is a rapidly evolving component of the immune system, which adapts to environmental threats. Lipid-reactive T cell subsets include, but are not limited to, CD1d-restricted invariant natural killer T (iNKT) cells (aka. type 1 NKT cells) and CD1d-restricted diverse NKT (dNKT) cells (aka. type 2 NKT cells), as well as other CD1-restricted lipid-reactive T cells, sometimes referred to as NKT-like cells, which are found in humans and other mammals, but not in mice. In addition, a new class of innate lymphocytes called mucosa-associated invariant T (MAIT) cells has attracted considerable attention recently due, at least in large part, to their antimicrobial characteristics. MAIT cells share several phenotypic and functional characteristics to lipid-reactive T cells. However, their invariant TCR is restricted by a ubiquitously expressed MHC class Ib molecule called MR1. Although much needs to be learned about their antigenic specificity, MAIT cells were recently shown to respond to microbe-derived vitamin B-based metabolites.
Despite recent progress in our understanding of CD1- and MR1-restricted T cells, much remains to be learned about their development and activation modes, the nature and range of antigens they recognize and their true potentials in immunotherapeutic applications for various diseases. Like in any other area of biology, uncertainties and controversies surrounding these cells and some of the experimental models employed to study them have brought about excitement and sometimes hot debates. The development of glycolipid-loaded CD1d tetramers about 15 years ago allowed tremendous strides in the study of type 1 NKT cells. Today, the emerging advent of improved or novel reagents holds the promise of generating new and important knowledge about CD1- and MR1-restricted T cells.
We plan to include between 10-15 articles reviewing the literature on the above cell types, covering controversies and pressing questions, and triggering constructive debates for the advancement of this intriguing and rapidly evolving area of immunobiology. We request that a section called “Outstanding Questions” be included in each article. Once all contributions are gathered, we will choose an image, ideally from a contributed article, to appear on the introductory page of the e-book to be produced. We will also jointly write a brief Editorial to introduce the topic and summarize the content of this issue of Frontiers in Immunology.
Lipid-reactive T cells are a heterogeneous population of T lymphocytes with unique specificities for glycolipid and lipid molecules presented in the context of major histocompatibility complex (MHC) class Ib molecules belonging to the CD1 family. They may recognize microbially encoded or synthetic lipids directly through their CD1-restricted T cell receptors (TCRs) or microbial components other than lipids including pathogen-associated molecular patterns (PAMPs) and bacterial superantigens. Once activated, lipid-reactive T cells participate as early effectors and/or regulators of immune responses. Immunoregulatory cytokines produced in copious amounts by these cells target a wide range of downstream effector cells and help shape the ensuing immune responses. The first CD1 molecule appeared around 300 million years ago, and has since diversified tremendously. Mammals comprise various numbers and isoforms of CD1 molecules, suggesting that lipid presentation is a rapidly evolving component of the immune system, which adapts to environmental threats. Lipid-reactive T cell subsets include, but are not limited to, CD1d-restricted invariant natural killer T (iNKT) cells (aka. type 1 NKT cells) and CD1d-restricted diverse NKT (dNKT) cells (aka. type 2 NKT cells), as well as other CD1-restricted lipid-reactive T cells, sometimes referred to as NKT-like cells, which are found in humans and other mammals, but not in mice. In addition, a new class of innate lymphocytes called mucosa-associated invariant T (MAIT) cells has attracted considerable attention recently due, at least in large part, to their antimicrobial characteristics. MAIT cells share several phenotypic and functional characteristics to lipid-reactive T cells. However, their invariant TCR is restricted by a ubiquitously expressed MHC class Ib molecule called MR1. Although much needs to be learned about their antigenic specificity, MAIT cells were recently shown to respond to microbe-derived vitamin B-based metabolites.
Despite recent progress in our understanding of CD1- and MR1-restricted T cells, much remains to be learned about their development and activation modes, the nature and range of antigens they recognize and their true potentials in immunotherapeutic applications for various diseases. Like in any other area of biology, uncertainties and controversies surrounding these cells and some of the experimental models employed to study them have brought about excitement and sometimes hot debates. The development of glycolipid-loaded CD1d tetramers about 15 years ago allowed tremendous strides in the study of type 1 NKT cells. Today, the emerging advent of improved or novel reagents holds the promise of generating new and important knowledge about CD1- and MR1-restricted T cells.
We plan to include between 10-15 articles reviewing the literature on the above cell types, covering controversies and pressing questions, and triggering constructive debates for the advancement of this intriguing and rapidly evolving area of immunobiology. We request that a section called “Outstanding Questions” be included in each article. Once all contributions are gathered, we will choose an image, ideally from a contributed article, to appear on the introductory page of the e-book to be produced. We will also jointly write a brief Editorial to introduce the topic and summarize the content of this issue of Frontiers in Immunology.
