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Review
. 2023 Apr 24:14:1117825.
doi: 10.3389/fimmu.2023.1117825. eCollection 2023.

Die Kämpfe únd schláchten-the struggles and battles of innate-like effector T lymphocytes with microbes

Sebastian Joyce  1   2 , Gosife Donald Okoye  2 , John P Driver  3
Affiliations
Review

Die Kämpfe únd schláchten-the struggles and battles of innate-like effector T lymphocytes with microbes

Sebastian Joyce et al. Front Immunol. .

Abstract

The large majority of lymphocytes belong to the adaptive immune system, which are made up of B2 B cells and the αβ T cells; these are the effectors in an adaptive immune response. A multitudinous group of lymphoid lineage cells does not fit the conventional lymphocyte paradigm; it is the unconventional lymphocytes. Unconventional lymphocytes-here called innate/innate-like lymphocytes, include those that express rearranged antigen receptor genes and those that do not. Even though the innate/innate-like lymphocytes express rearranged, adaptive antigen-specific receptors, they behave like innate immune cells, which allows them to integrate sensory signals from the innate immune system and relay that umwelt to downstream innate and adaptive effector responses. Here, we review natural killer T cells and mucosal-associated invariant T cells-two prototypic innate-like T lymphocytes, which sense their local environment and relay that umwelt to downstream innate and adaptive effector cells to actuate an appropriate host response that confers immunity to infectious agents.

Keywords: MAIT (mucosal-associated invariant T) cell; NKT (natural killer T) cell; innate-like effector lymphocyte; pathobiont; symbionts.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Innate-like effector lymphocyte functions mirror type 1, type 2, and type 3 effector cells. Natural killer T (NKT), mucosal-associated invariant T (MAIT), and γδT cells are characterized by semi-invariant T-cell receptor (TCR) expression by contrast to conventional T cells express a diverse TCR (IMGT nomenclature) repertoire. By contrast, innate lymphoid cells and NK cells do not express rearranged antigen receptors. Type 1 effectors include the cytotoxic NK and CD8+ T cells and T helper (Th) 1 cells, as well as NKT1, MAIT1, and γδT1 cells. They require IL-12 for induction, which is bolstered by IFN-γ. T-bet and the related eomesodermin transcription factors control the differentiation of type 1 effector cells, which are essential for immunity against intracellular pathogens. Type 2 effector cells include Th2, NKT2, and γδT2 cells. These cells are activated by IL-4 and require GATA3 for their effector differentiation. Their physiologic functions—e.g., parasite expulsion, and pathologic—e.g., airway hypersensitivity, are mediated by IL-4, IL-5, and IL-13 secretions. RORγt—the lineage specific transcription factor program type 3 effectors, which include Th17 and NKT17, MAIT17, and γδT17 cells. Lineage-specific inducive factors include IL-6, TGF-β, IL-1β, IL-23, and IL-7. Type 3 effector cells secrete IL-17 and IL-22 upon activation, by which they mediate tissue repair and confer immunity to extracellular bacteria and fungi.
Figure 2
Figure 2
Immune functions of mouse NKT cells. NKT cell activation is initiated by semi-invariant NKT cell receptor interactions with cognate antigen and bolstered by costimulatory interactions between CD28 and CD40 and their cognate ligands CD80/86 (B7.1/7.2) and CD40L, respectively. The resulting activated NKT cells crosstalk with members of the innate and the adaptive immune systems by deploying cytokine and chemokine messengers. Upon activation in vivo, NKT cells rapidly secrete a variety of cytokines and chemokines, which influence the polarization of CD4+ T cells toward Th1 or Th2 cells as well as the differentiation of precursor CD8+ T cells to effector lymphocytes, and B cells to antibody-secreting plasma cells. Some of these mediators facilitate the recruitment, activation, and differentiation of macrophages and DCs, which results in the production of interleukin (IL)-12 and possibly other factors. IL-12, in turn, stimulates NK cells to secrete IFN-γ. Thus, activated NKT cells have the potential to enhance as well as temper the immune response. This schematic rendition is an adaptation of past reviews (, –41) and works cited in the text.
Figure 3
Figure 3
Modes of NKT and MAIT cell activation by microbes. Potent agonists—such as αGalCer, directly activate NKT cells, without the need for a second signal, in a TCR signaling–dominated fashion (left panel). Alternatively, microbes containing TLR ligands such as LPS activate NKT cells by inducing IL-12 production by DCs, which amplifies weak responses elicited upon the recognition of CD1d bound with self-glycolipids by the NKT cell TCR. Several endogenous lipid agonists have been identified and characterized (see Table 1 ). Some microbes—such as Sphingomonas capsulata and Borrelia burgdorferi—synthesize α-anomeric glycolipids for their cell walls. These glycolipids, when presented by CD1d, weakly activate NKT cells directly. In the presence of a second signal—generally a proinflammatory cytokine such as IL-12, such weak agonists strongly activate NKT cells (middle panel). By contrast, the mode of MAIT cell activation appears to be agonist concentration dependent: microbes that produce high levels of 5-OP-RU—a product of ribD-controlled catalytic activity, directly activate MAIT cells, while those that produce low levels of 5-OP-RU require a cytokine boost. Unlike conventional T cells, cytokines alone can activate both NKT and MAIT cells. Such cytokines, which include a combination of IL-12 and IL-18, activate NKT cells in a TCR-independent manner (right panel). This diagram renders the different strategies for NKT cell activation; they apply to MAIT cells as well. Similarities and differences, if any, are described in the text. Adapted from past reviews (35, 37, 38, 41) and works cited in the text.
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