NKT Cells Contribute to the Control of Microbial Infections

Abstract

Innate (-like) T lymphocytes such as natural killer T (NKT) cells play a pivotal role in the recognition of microbial infections and their subsequent elimination. They frequently localize to potential sites of pathogen entry at which they survey extracellular and intracellular tissue spaces for microbial antigens. Engagement of their T cell receptors (TCRs) induces an explosive release of different cytokines and chemokines, which often pre-exist as constitutively expressed gene transcripts in NKT cells and underlie their poised effector state. Thus, NKT cells regulate immune cell migration and activation and subsequently, bridge innate and adaptive immune responses. In contrast to conventional T cells, which react to peptide antigens, NKT cells recognize lipids presented by the MHC class I like CD1d molecule on antigen presenting cells (APCs). Furthermore, each NKT cell TCR can recognize various antigen specificities, whereas a conventional T lymphocyte TCR reacts mostly only to one single antigen. These lipid antigens are either intermediates of the intracellular APC`s-own metabolism or originate from the cell wall of different bacteria, fungi or protozoan parasites. The best-characterized subset, the type 1 NKT cell subset expresses a semi-invariant TCR. In contrast, the TCR repertoire of type 2 NKT cells is diverse. Furthermore, NKT cells express a panoply of inhibitory and activating NK cell receptors (NKRs) that contribute to their primarily TCR-mediated rapid, innate like immune activation and even allow an adaption of their immune response in an adoptive like manner. Dueto their primary localization at host-environment interfaces, NKT cells are one of the first immune cells that interact with signals from different microbial pathogens. Vice versa, the mutual exchange with local commensal microbiota shapes also the biology of NKT cells, predominantly in the gastrointestinal tract. Following infection, two main signals drive the activation of NKT cells: first, cognate activation upon TCR ligation by microbial or endogenous lipid antigens; and second, bystander activation due to cytokines. Here we will discuss the role of NKT cells in the control of different microbial infections comparing pathogens expressing lipid ligands in their cell walls to infectious agents inducing endogenous lipid antigen presentation by APCs.

Keywords: NKT cells; bystander activation; cognate activation; lipid antigens; microbial infection; tissue homeostasis.

Figure 1

Modes of NKT cell activation upon bacterial infection. Following the uptake and digestion of bacteria by myeloid cells, three mechanisms predominantly drive the activation of NKT cells: (A), bacterial cell wall glycosphingolipid (GSL) antigens presented by APCs are sufficient to induce the release of IFN-γ and IL-4 by NKT cells due to the CD1d mediated presentation of the ligand to the NKT cell TCR. (B), endogenous GSL presentation via CD1d to the NKT cell TCR in response to infection and subsequent augmented NKT cell auto-reactivity. The identity of the lipid ligands underlying the auto-reactivity of NKT cells in different tissues and under distinct (patho-) physiological circumstances, however, still requires definition. (C), the cytokine driven, TCR-independent activation of NKT cells for which TLR- oder Dectin triggered IL-12 and IL-18 release by APCs is responsible. This also further enhances the release of cytokines by NKT cells, activated by cognate TCR engagement [mechanisms (A, B)]. Thus, NKT cells are activated during infection with bacteria that do not express themselves NKT cell antigens in their cell walls or unable to induce endogenous antigens.

Figure 2

Effects of NKT cell activation on B-lymphocytes and NK cells. NKT cells and antigen presenting cells such as B-lymphocytes (A) or DCs (B) influence each other due to cognate and bystander activation. Thus, on the one hand, B-lymphocytes and DCs can modify NKT cell responses due to variations in the presentation of lipid antigens and/or an altered release of cytokines and/or changes in the expression of costimulatory molecules. B cells can promote thereby also Th2 responses (A), whereas DCs presumably trigger predominantly the release of Th1 cytokines (B). Vice versa, dependent on the interaction with cytokines, costimulatory molecules and/or the lipid antigens presented, NKT cells, for example, can alter their cytokine profile (Th1 and Th2) and subsequently suppress or augment B cell responses. This can affect the release and/or the class switch of antibodies by B-lymphocytes (A) or the cytokine profile and/or expression of costimulatory molecules by DCs (B). Within a more Th1-dominated cytokine milieu, NKT cells can cross-activate NK cells and CD8⁺ T-lymphocytes (C), a process that involves IFN-γ. This release of cytokines by NKT cells, however, does not only augment subsequent immune responses, but can also contribute to immunosuppression, for example, due to the upregulation of mTOR.