Innate lymphoid cells (ILC) are a newly appreciated immune cell subset that are important in health and disease. Previous reports have shown NKp44+ type 3 ILC (ILC3) that are important sources of IL-17 and IL-22 are depleted in gut tissues in HIV and SIV infection, yet it is unclear how HIV infection affects the frequencies or function of ST2+ ILC2 that secrete IL-13 or ILC1 that secrete IFN-g. Finally, the role of microbial translocation on ILC survival and function is poorly understood.
In non-human primate models of HIV infection, we assessed the frequencies of ILC subsets in gut-draining mesenteric lymph nodes (MLN) by flow cytometry and IL-17, IL-13, and IFN-g production by PMA/ionomycin treatment. To determine the role of microbial translocation on ILC frequency and function, we treated healthy uninfected rhesus macaques (RM) with DSS to induce chronic gut barrier damage.
Bulk CD4 T cells or IL-17+ CD4 T cells (Th17) in the MLN were not lost at early infection time points (day 10-14dpi), yet NKp44+ ILC3 in acutely infected RM (N=8) were significantly depleted (mean ILC3=0.03%) when compared to ILC3 of uninfected RM (N=10)(mean ILC3= 0.12%)(p=0.007). No significant differences in frequencies of ST2+ ILC2 or ILC1 were observed between acutely infected and uninfected RM. While caspase-3 expression of MLN CD4 T cells was unchanged, caspase-3 expression was elevated in ILC1 (mean caspase-3=12%), ILC2 (mean caspase-3=24%), and ILC3 (mean caspase-3=4%) subsets in acutely infected animals when compared to caspase-3 expression in these ILC subsets in MLN of healthy animals (pILC1=0.001)(pILC2=0.04)(pILC3=0.002). ILC3 in chronic SIV+ MLN secreted more IL-17 (mean IL-17=30.5%) than NKp44+ ILC3 from uninfected RMs when stimulated (mean IL-17= 6.6%)(p=0.004). When healthy animals were treated with DSS to induce microbial translocation (N=4), frequencies of all ILC subsets remained unchanged yet ILC3 secreted more IL-17 (mean IL-17= 33%) than ILC3 from uninfected RM (mean IL-17=6.6%)(p=0.009).
Depletion of NKp44+ ILC3 and elevated apoptosis in all ILC subsets in the MLN is surprising given that this precedes MLN CD4 T cell death and ILCs are not permissive to SIV infection. Microbial products alone may not contribute to ILC loss, yet may augment IL-17 production in ILC3 as this is apparent in settings of microbial translocation with and without viral replication.