Are human iNKT cells keeping tabs on lipidome perturbations triggered by oxidative stress in the blood?

Abstract

The central paradigm of conventional MHC-restricted T cells is that they respond specifically to foreign peptides, while displaying tolerance to self-antigens. In contrast, it is now becoming clear that a number of innate-like T cell subsets-CD1-restricted T cells, Vγ9Vδ2 T cells, and MAIT cells-may operate by different rules: rather than focusing on the recognition of specific foreign antigens, these T cells all appear to respond to alterations to lipid-related pathways. By monitoring perturbations to the "lipidome," these T cells may be able to spring into action to deal with physiological situations that are of self as well as microbial origin. iNKT cells are a prime example of this type of lipidome-reactive T cell. As a result of their activation by self lyso-phospholipid species that are generated downstream of blood lipid oxidation, human iNKT cells in the vasculature may respond sensitively to a variety of oxidative stresses. Some of the cytokines produced by activated iNKT cells have angiogenic effects (e.g., GM-CSF, IL-8), whereas others (e.g., IFN-γ) are pro-inflammatory factors that can propagate vascular pathology by influencing the functions of macrophages and dendritic cells. Consistent with this, evidence is accumulating that iNKT cells contribute to atherosclerosis, which is one of the most common inflammatory pathologies, and one that is integrally related to characteristics of the lipidome.

T Cell Receptor Repertoire Analysis Reveals Signatures of T Cell Responses to Human Mycobacterium tuberculosis

“…Meanwhile, CD1-restricted T cells, responded to alterations to lipid-related pathways. Guo et al (2018) found that naive CD4 + T cells was activated after stimulated by CD1c + APC presenting lipids and preferentially expressed TRBV4-1 + TCRs, which was confirmed as CD1c-restricted autoreactivity (Felley and Gumperz, 2016). Studies have shown that bacterial phospholipids can activate CD1-restricted T cells by binding directly to CD1 from antigen-presenting cells and TCRs, which preferentially express TRBV4-1 + TCRs, thus emphasizing a mechanism for CD1-mediated T cell activation to protect against Mtb infection (Kasmar et al, 2011;Van Rhijn and Moody, 2015;Shahine et al, 2017;Guo et al, 2018;Reinink et al, 2019;Tezera et al, 2020).…”

The Pathophysiological Relevance of the iNKT Cell/Mononuclear Phagocyte Crosstalk in Tissues

“…Regulatory iNKT10 cells are selectively enriched in the AT and rapidly respond to stimulatory lipids presented by CD1d+ macrophages, or adipocytes, by secreting IL-4 that restrains M1 and promotes M2 polarization ( 25 , 35 , 83 , 85 , 86 ). However, a prolonged dysmetabolic state provokes down-regulation of CD1d on AT-M2 cells and their switch to an M1-like phenotype that, in turn, leads also to a pro-inflammatory shift of local iNKT cells ( 83 , 87 , 88 ), again suggesting a plasticity due to the migration of iNKT1 cells from other sites or a functional differentiation of local cells. The presence of iNKT cells in the AT, which is conserved between mouse and human, is crucial for the formation of fat-associated lymphoid clusters (FALC).…”

The lysophospholipid‐binding molecule CD1D is not required for the alloimmunization response to fresh or stored RBCs in mice despite RBC storage driving alterations in lysophospholipids

“…It has become increasingly clear that the immune system has evolved the ability to recognize and respond to changes in various lipid moieties through a number of innate-like T-cell subsets. 17 Chief among these are NK T cells (NKT), which are able to respond to changes in lipid species via their recognition of a wide variety of self and non-self lysophospholipid species bound to the nonclassical MHC molecule CD1D. 18,19 NKT recognition of lipids bound to CD1D has been shown to play a role in controlling immune responses in multiple different contexts including atheroschlerosis, [20][21][22] multiple models of autoimmunity, 23 cancer, 24 as well as bacterial, mycobacterial, and fungal infections.…”

“…One potential source of DAMPs is altered endogenous lipids that occur during RBC storage. It has become increasingly clear that the immune system has evolved the ability to recognize and respond to changes in various lipid moieties through a number of innate‐like T‐cell subsets 17 . Chief among these are NK T cells (NKT), which are able to respond to changes in lipid species via their recognition of a wide variety of self and non‐self lysophospholipid species bound to the nonclassical MHC molecule CD1D 18,19 .…”