CD1d- and MR1-Restricted T Cells in Sepsis

Abstract

Dysregulated immune responses to infection, such as those encountered in sepsis, can be catastrophic. Sepsis is typically triggered by an overwhelming systemic response to an infectious agent(s) and is associated with high morbidity and mortality even under optimal critical care. Recent studies have implicated unconventional, innate-like T lymphocytes, including CD1d- and MR1-restricted T cells as effectors and/or regulators of inflammatory responses during sepsis. These cell types are typified by invariant natural killer T (iNKT) cells, variant NKT (vNKT) cells, and mucosa-associated invariant T (MAIT) cells. iNKT and vNKT cells are CD1d-restricted, lipid-reactive cells with remarkable immunoregulatory properties. MAIT cells participate in antimicrobial defense, and are restricted by major histocompatibility complex-related protein 1 (MR1), which displays microbe-derived vitamin B metabolites. Importantly, NKT and MAIT cells are rapid and potent producers of immunomodulatory cytokines. Therefore, they may be considered attractive targets during the early hyperinflammatory phase of sepsis when immediate interventions are urgently needed, and also in later phases when adjuvant immunotherapies could potentially reverse the dangerous state of immunosuppression. We will highlight recent findings that point to the significance or the therapeutic potentials of NKT and MAIT cells in sepsis and will also discuss what lies ahead in research in this area.

Effect of PD-1

“…iNKT-cells play key regulatory roles in a diversity of diseases including viral and bacterial infections, cancer surveillance and autoimmune diseases(1-3, 6). It is being increasingly demonstrated that iNKT-cells play a key role in coordinating this immune response in both experimental sepsis as well as in critically ill septic patients.…”

“…However, unlike thymic NKT cells, non-thymic NKT-cells do not require ongoing CD1d interaction for homeostasis, proliferation or survival in their tissue beds(30). Rather, the cytokine milieu as well as the tissue locale in which the iNKT-cells are found, liver versus spleen, may be just as important in influencing iNKT-cell function(3, 27, 30, 31). …”

“…Although our understanding of the control of immune cell migration in general, is growing, there remains a paucity of information pertaining to the regulation of key innate regulatory immune cells. Invariant Natural Killer T-cells (iNKT-cells) are innate lymphocytes that are emerging as key regulators of the immune response to a variety of diseases, including cancer, autoimmune disorders, as well as sepsis(1-3). Specifically, we have demonstrated a role for hepatic iNKT cells in modulating both the systemic response to sepsis as well as the phagocytic response(1, 4).…”

Deficiencies of Circulating Mucosal-associated Invariant T Cells and Natural Killer T Cells in Patients with Multiple Trauma

“…Recent studies have implicated 2 distinct unconventional, innate-like T lymphocytes, such as MR1-restricted mucosal-associated invariant T (MAIT) cells and CD1d-restricted natural killer T (NKT) cells as effectors and/or regulators of inflammatory responses during sepsis (4). These cell types express an invariant T cell receptor (TCR) Vα7.2-Jα33 chain paired with a limited repertoire of Vβ chains or an invariant TCR pair of Vα24-Jα18/Vβ11 chains together with the Vβ chain, respectively (5).…”

The interaction between invariant Natural Killer T cells and the mucosal microbiota

“…110 On the other hand, the impact of the microbiota is not limited to the mucosal surfaces and can influence apparently any part of the body, including seemingly remote areas, such as the brain. 111 With regard to iNKT cells, the above-mentioned systemic effects of antibiotic treatment and the role of iNKT cells are relevant in sepsis, 112 which is often caused by translocated intestinal bacteria. 113 Furthermore, one member of the commensal Sphingobium species (Novosphingobium aromaticivorans) has been linked to iNKT celldependent autoimmune responses against the bile duct in mice 53 and humans.…”