Interleukin-22: immunobiology and pathology

Abstract

Interleukin-22 (IL-22) is a recently described IL-10 family cytokine that is produced by T helper (Th) 17 cells, γδ T cells, NKT cells, and newly described innate lymphoid cells (ILCs). Knowledge of IL-22 biology has evolved rapidly since its discovery in 2000, and a role for IL-22 has been identified in numerous tissues, including the intestines, lung, liver, kidney, thymus, pancreas, and skin. IL-22 primarily targets nonhematopoietic epithelial and stromal cells, where it can promote proliferation and play a role in tissue regeneration. In addition, IL-22 regulates host defense at barrier surfaces. However, IL-22 has also been linked to several conditions involving inflammatory tissue pathology. In this review, we assess the current understanding of this cytokine, including its physiologic and pathologic effects on epithelial cell function.

Keywords: epithelial cells; interleukin-22; tissue regeneration.

Figure 1. Receptors and JAK-STAT molecules of the IL-10 family of cytokines

IL-22 is a member of the IL-10 family of cytokines, all of which share common features in their receptors. IL-22R is composed of two subunits: the common IL10R2 subunit, which is shared with the receptors for IL10, IL-26, IL-28 and IL-29; and the IL-22R1 subunit, which itself can also pair an IL-20R2 subunit forming the receptor for IL-20 and IL-24. IL-20 and IL-24 (in addition to IL-19) can also signal through another receptor composed of IL-20R1 and IL-20R2. Each of these receptors signals through components of the JAK-STAT pathway, although there is evidence that IL-22 can also signal through p38 and MAP kinase pathways.

Figure 2. Cellular sources of IL-22 and their lineage relationships

All IL-22 producing cells derive from a hematopoietic stem cell located in the bone marrow (BM). TH17 cells, γδ T cells and NKT cells develop in the thymus, branching off from conventional T cell development at different stages: NKT cells at the DN3 stage of thymocyte development; γδ T cells upon TCR rearrangement; and TH17 cells at the naïve T cell stage outside the thymus. All ILCs derive from a common ckit+IL7Rα+ common lymphoid progenitor (CLP). Several recent papers have described ILC precursors (pILC) with varying capacity for differentiation. An NFIL3+ pILC has recently been described with the capacity to differentiate into all ILC subsets as well as conventional NK cells. This precursor gives rise to an Id2+ cell giving rise to all ILC populations except for NK cells. A PLZF+ pILC has also been described, differentiating into ILC1, ILC2 and NCR+ ILC3, but not into conventional NK cells or into NCR− ILC3. Evidence also suggests that NCR− group 3 ILC can differentiate into NCR+ ILC3. Solid lines represent known, and dashed lines represent putative, progenitor-progeny relationships.

Figure 3. Target tissues and physiological effects of IL-22

A role for IL-22 has been described in numerous tissues including gut, liver, lung, skin, thymus, kidney, heart, pancreas and synovial tissue. IL-22R is expressed on epithelial cells and some fibroblasts in those tissues. IL-22 can promote their cellular proliferation, resistance to apoptosis, and wound healing. In barrier organs such as gut, lung and skin, IL-22 also promotes the production of antimicrobial molecules such as S100, Reg3β and Reg3γ, as well as defensins, thereby aiding in host defense and barrier function. IL-22 is important for promoting tissue regeneration after injury in several organs. However, studies have also indicated that IL-22 is associated with malignancies of the skin, thyroid, breast, stomach, pancreas, liver, cervix and colon, as well as other inflammatory pathology including psoriasis. In BMT, ILC-derived IL-22 is important for tissue regeneration after injury caused by alloreactive T cells, however, there is also some evidence that IL-22 produced by donor T cells can contribute to inflammation and GVHD pathology.