Summary Little is known about the maintenance of intestinal stem cells (ISCs) and progenitors during immune-mediated tissue damage or about the susceptibility of transplant recipients to tissue damage mediated by the donor immune system during graft vs. host disease (GVHD). We demonstrate here that deficiency of recipient-derived IL-22 increased acute GVHD tissue damage and mortality, that ISCs were eliminated during GVHD, and that ISCs as well as their downstream progenitors expressed the IL-22 receptor. Intestinal IL-22 was produced after bone marrow transplant by IL-23-responsive innate lymphoid cells (ILCs) from the transplant recipients, and intestinal IL-22 increased in response to pre-transplant conditioning. However, ILC frequency and IL-22 amounts were decreased by GVHD. Recipient IL-22 deficiency led to increased crypt apoptosis, depletion of ISCs, and loss of epithelial integrity. Our findings reveal IL-22 as a critical regulator of tissue sensitivity to GVHD and a protective factor for ISC during inflammatory intestinal damage.

Endogenous thymic regeneration is a crucial function that allows for renewal of immune competence after stress, infection or immunodepletion. The mechanisms governing this regeneration, however, remain poorly understood. Here we detail a framework of thymic regeneration centred on IL-22 and triggered by depletion of CD4+CD8+ double positive (DP) thymocytes. Intrathymic levels of IL-22 were increased following thymic insult, and thymic recovery was impaired in IL-22-deficient mice. IL-22, which signalled through thymic epithelial cells (TECs) and promoted their proliferation and survival, was upregulated by radio-resistant RORγ(t)+CCR6+NKp46− lymphoid tissue-inducer cells (LTi) after thymic injury in an IL-23 dependent manner. Importantly, administration of IL-22 enhanced thymic recovery following total body irradiation (TBI). These studies reveal mechanisms of endogenous thymic repair and offer innovative regenerative strategies for improving immune competence.

IntroductionThus far, 3 subsets of proinflammatory helper T cells have been described: Th1, Th2, and Th17 cells. 1 Naive T cells exposed to interleukin-12 1 (IL-12) differentiate into Th1 cells, resulting in expression of Tbet and STAT4, and secretion of interferon (IFN)-␥. 2 Th1 cells are essential for the clearance of intracellular bacteria and negatively regulate the development of Th2 and Th17 cells. 2 IL-4 activates a Th2 program, characterized by expression of STAT6 and GATA3 and secretion of IL-4, IL-5, and IL-13, which is important for humoral immunity. 2 Finally, naive T cells exposed to TGF-␤, IL-6, and IL-21 differentiate into Th17 cells by activating ROR␥t, ROR␣, STAT3, STAT4, and IRF4 transcription factors. [3][4][5][6] Th17 cells produce high levels of IL-17A (IL-17), IL-17F, IL-21, and IL-22, and have been shown to contribute to mucosal immunity. [7][8][9] Specifically, IL-17 is important in the control or clearance of various pathogens, including Klebsiella pneumoniae, 10 Citrobacter rodentium, 3 Borrelia burgdorferi, 11 and Candida albicans. 12 In addition, Th17 cells have been implicated in allograft rejection of solid organs [13][14][15] and several autoimmune diseases. 1,[16][17][18][19] IL-17, otherwise known as IL-17A, is the bestcharacterized member of the IL-17 family (IL-17A through F). IL-17 is a disulfide-linked homodimeric glycoprotein consisting of 155 amino acids with a molecular weight of 35 kDa. 20 IL-17F shares the greatest homology with IL-17 (55%). Th17 cells produce IL-17 and IL-17F while innate immune cells produce other IL-17 family members. IL-17 and IL-17F can exist as homodimers or heterodimers. 21 IL-17 homodimers are efficient at inducing chemokine production by epithelial cells. The IL-17 receptor (IL-17RA) is a type 1 transmembrane protein, and its mRNA is expressed in the lungs, kidneys, liver, and spleen as well as in isolated fibroblasts, epithelial cells, mesothelial cells, and various myeloid cells in rats and mice. 20 Th17 cells have been identified as the primary source of IL-22, an IL-10 family member. 8,22 IL-22 can stimulate proliferation, abnormal differentiation, and migration of various epithelial cells. 23 Its up-regulation has been associated with several autoimmune diseases, including psoriasis, Crohn's disease, and ulcerative colitis, as well as murine models of inflammatory bowel disease. [24][25][26][27] Allogeneic bone marrow transplantation (BMT) is a potentially curative therapy for various hematopoietic malignancies and immunologic diseases. 28,29 GVHD is a major complication of allogeneic BMT and causes significant morbidity and mortality. GVHD is the result of alloreactive donor T cells recognizing alloantigens on normal host tissues and mounting an attack against the host. 28,30 During GVHD, donor T cells specifically target the intestines, skin, and liver, 28 however, alloreactive T cells also contribute to graft-versus-tumor (GVT) activity, which may prevent tumor relapse. 28 During the early stages after BMT, alloreactive CD4 ϩ T cells sec...