Interleukin-22 (IL-22) is a cytokine with epithelial reparative and regenerative properties that is produced by Th22 cells and by other immune cell subsets. Therefore, we explored the hypothesis that disruption of the gut barrier during HIV infection involves dysregulation of these cells in the gastrointestinal mucosa. Sigmoid IL-22-producing T cell and Th22 cells were dramatically depleted during chronic HIV infection, epithelial integrity was compromised, and microbial translocation was increased. These alterations were reversed after long-term antiretroviral therapy. While all mucosal IL-22-producing T-cell subsets were also depleted very early during HIV infection, at these early stages IL-22 production by non-T-cell populations (including NKp44+ cells) was increased and gut epithelial integrity was maintained. Circulating Th22 cells expressed a higher level of the HIV co-receptor/binding molecules CCR5 and α4β7 than CD4+ T-cell subsets in HIV-uninfected participants, but this was not the case after HIV infection. Finally, recombinant IL-22 was protective against HIV and tumor necrosis factor-α-induced gut epithelial damage in a validated in vitro gut epithelial system. We conclude that reduced IL-22 production and Th22 depletion in the gut mucosa are important factors in HIV mucosal immunopathogenesis.

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Tumour budding in colorectal cancer is an important prognostic factor. A recent consensus conference elaborated recommendations and key issues for future studies, among those the use of pan‐cytokeratin stains, especially in stage II patients. We report the first prospective diagnostic experience using pan‐cytokeratin for tumour budding assessment. Moreover, we evaluate tumour budding using pan‐cytokeratin stains and disease‐free survival (DFS) in stage II patients. To this end, tumour budding on pan‐cytokeratin‐stained sections was evaluated by counting the number of tumour buds in 10 high‐power fields (0.238 mm2), then categorizing counts as low/high‐grade at a cut‐off of 10 buds, in two cohorts. Cohort 1: prospective setting with 236 unselected primary resected colorectal cancers analysed by 17 pathologists during diagnostic routine. Cohort 2: retrospective cohort of 150 stage II patients with information on DFS. In prospective analysis of cohort 1, tumour budding counts correlated with advanced pT, lymph node metastasis, lymphovascular invasion, perineural invasion (all p < 0.0001), and distant metastasis (p = 0.0128). In cohort 2, tumour budding was an independent predictor of worse DFS using counts [p = 0.037, HR (95% CI): 1.007 (1.0–1.014)] and the low‐grade/high‐grade scoring approach [p = 0.02; HR (95% CI): 3.04 (1.2–7.77), 90.7 versus 73%, respectively]. In conclusion, tumour budding assessed on pan‐cytokeratin slides is feasible in a large pathology institute and leads to expected associations with clinicopathological features. Additionally, it is an independent predictor of poor prognosis in stage II patients and should be considered for risk stratification in future clinical studies.