Role of innate lymphocytes in infection and inflammation

Abstract

Cooperation between the innate and adaptive immune responses is critical for enabling protective immunity against various invading microbes. Distinct types of effector T cells have different functions in adaptive immune responses. Th1 cells play important roles in the control of intracellular bacteria by producing IFN-γ to activate macrophages and in anti-viral immunity by producing IFN-γ and activating cytotoxic T lymphocytes. Th2 cell-derived cytokines are important in activating mast cells, eosinophils, and goblet cells in anti-helminth immunity. Th17 cells are pivotal for the inflammatory response mediated by neutrophils, which resists extracellular bacterial infection. In all cases, it is critical that the innate immune responses limit the growth and expansion of invading microbes until antigen-specific adaptive immune responses are established. Recent studies have identified multiple subsets in innate lymphocytes corresponding to previously defined Th subsets. Classical natural killer cells, RORγ(+) lymphoid tissue inducer-related cells, and Th2-type innate lymphocytes play distinct roles in innate immune responses by producing Th1, Th17, and Th2 cytokines, respectively. Cooperation between innate lymphocytes and antigen-specific T and B cells are likely important in protective immunity against distinct types of microbes. The most recently identified subset is the RORγ-independent Lin(-)Thy-1(+)IL-7R(+)GATA3(+) innate lymphocyte subset such as natural helper (NH) cell, which is Id2- and IL-7-dependent. This population produces Th2 cytokines, most notably IL-5 and IL-13, and plays a major role in innate immune responses during anti-helminth immunity. In addition, these cells are likely involved in the pathophysiology of some types of allergic diseases. We summarize here current knowledge regarding various innate lymphocyte subsets. In particular, we focus on the Th2-type innate lymphocyte subset.

Keywords: Th2 cytokine; allergic inflammation; asthma; fat-associated lymphoid cluster; helminth; innate helper type 2; natural helper cell; nuocyte.

Figure 1

Cytokine-producing cells in innate and adaptive immune systems. Just as for Th1, Th2, and Th17 cells in the adaptive immune system, NK cells, Th2-type innate lymphocytes and LTi cells play distinct roles in innate immune responses by producing Th1, Th2, and Th17 cytokines, respectively.

Figure 2

Developmental relationships between various innate lymphocytes. Cytokines and transcription factors involved in the differentiation of innate lymphocyte subsets are shown. The plasticity of RORγ⁺ LTi-related innate lymphocytes is noted as shown here but the relationship between NH cells and nuocytes is currently unknown.

Figure 3

Functions of NH cells. (A) IL-5 and IL-6 constitutively produced by NH cells support IgA production by B cells. IL-5 supports the growth of B1 cells in the peritoneal cavity. (B) Upon helminth infection, IL-33 produced by epithelial cells, endothelial cells, and/or adipocytes induces high levels of IL-5 and IL-13 by NH cells, resulting in eosinophilia and goblet cell hyperplasia, which play important roles in an early phase of anti-helminth immune responses. Similarly, a combination of IL-2 and IL-25 (IL-2 + IL-25) also induces large amounts of IL-5 and IL-13 from NH cells.