Invariant NKT cells: regulation and function during viral infection

Abstract

Natural killer T cells (NKT cells) represent a subset of T lymphocytes that express natural killer (NK) cell surface markers. A subset of NKT cells, termed invariant NKT cells (iNKT), express a highly restricted T cell receptor (TCR) and respond to CD1d-restricted lipid ligands. iNKT cells are now appreciated to play an important role in linking innate and adaptive immune responses and have been implicated in infectious disease, allergy, asthma, autoimmunity, and tumor surveillance. Advances in iNKT identification and purification have allowed for the detailed study of iNKT activity in both humans and mice during a variety of chronic and acute infections. Comparison of iNKT function between non-pathogenic simian immunodeficiency virus (SIV) infection models and chronic HIV-infected patients implies a role for iNKT activity in controlling immune activation. In vitro studies of influenza infection have revealed novel effector functions of iNKT cells including IL-22 production and modulation of myeloid-derived suppressor cells, but ex vivo characterization of human iNKT cells during influenza infection are lacking. Similarly, as recent evidence suggests iNKT involvement in dengue virus pathogenesis, iNKT cells may modulate responses to a number of emerging pathogens. This Review will summarize current knowledge of iNKT involvement in responses to viral infections in both human and mouse models and will identify critical gaps in knowledge and opportunities for future study. We will also highlight recent efforts to harness iNKT ligands as vaccine adjuvants capable of improving vaccination-induced cellular immune responses.

Figure 1. Surface marker and cytokine expression of human iNKT cell subsets.

Both subsets express CD161, α4β7, and high levels of CXCR4. CD4+ iNKTs preferentially express CCR4 and CD62L, and produce both Th1 and Th2 cytokines. CD4− iNKTs preferentially express chemokine receptors CCR1, CCR6, and CXCR6, as well as CD11a and NKG2D. This subset secretes predominately Th1 cytokines and more quickly secretes perforin than the CD4+ subset.

Figure 2. iNKT regulation of NK, T cell, and B cell activation.

Presentation of lipid antigen to iNKT cells by DCs leads to iNKT activation and upregulation of CD40L. CD40–CD40L interactions and iNKT cytokine secretion promotes DC activation and maturation, which in turn leads to antigen cross-presentation and augmentation of CD4+ and CD8+ T cell responses. iNKT IFNγ secretion rapidly activates NK cells and induces further IFNγ secretion. iNKTs can substitute for CD4+ T cell help in B cell activation through CD40–CD40L interactions, and iNKT activation improves antibody titres and B cell memory responses. Finally, iNKT production of IL-2 induces regulatory T cell (Treg) proliferation, while Tregs can also inhibit iNKT proliferation and functional responses.

Figure 3. iNKT modulation of myeloid-derived suppressor cells (MDSCs) elicited during influenza A infection.

Influenza infection leads to the expansion of the MDSC population (comprised of immature dendritic cells, immature macrophages, and granulocytes), which can inhibit T cell proliferation in vivo and in vitro. iNKT cells suppress both the expansion of the MDSCs and the suppressive effect of MDSCs in a CD40-CD40L-dependent manner .