NK cells are essential for controlling viral infections. We investigated NK cell and innate lymphoid cell (ILC) dynamics and function in rhesus macaque rectal tissue and blood following mucosal priming with replicating adenovirus (Ad)-SIV recombinants, systemic boosting with SIV envelope protein, and subsequent repeated low-dose intravaginal SIV exposures. Mucosal memory-like NK and ILC subsets in rectal and vaginal tissues of chronically infected macaques were also evaluated. No differences in NK cell or ILC frequencies or cytokine production were seen between vaccinated and Ad-empty/alum controls, suggesting responses were due to the Ad-vector and alum vaccine components. Mucosal NKp44⁺ ILCs increased postvaccination and returned to prelevels postinfection. The vaccine regimen induced mucosal SIV-specific Ab, which mediated Ab-dependent cellular cytotoxicity and was correlated with mucosal NKp44⁺CD16⁺ ILCs. Postvaccination NKp44⁺ and NKp44⁺IL-17⁺ ILC frequencies were associated with delayed SIV acquisition and decreased viremia. In chronically SIV-infected animals, NKp44⁺ ILCs negatively correlated with viral load, further suggesting a protective effect, whereas, NKG2A^- NKp44^- double-negative ILCs positively correlated with viral load, indicating a pathogenic role. No such associations of circulating NK cells were seen. Δγ NK cells in mucosal tissues of chronically infected animals exhibited impaired cytokine production compared with non-Δγ NK cells but responded to anti-gp120 Ab and Gag peptides, whereas non-Δγ NK cells did not. Mucosal Δγ NKp44⁺ and Δγ DN cells were similarly associated with protection and disease progression, respectively. Thus, the data suggest NKp44⁺ ILCs and Δγ cells contribute to SIV infection outcomes. Vaccines that promote mucosal NKp44⁺ and suppress double-negative ILCs are likely desirable.

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