While loss of intestinal homeostasis can be driven by genetic lesions, environmental factors, or treatment-associated side effects that precipitate inflammatory disease, a perhaps more common trigger for dysregulated intestinal homeostasis is infection. Indeed, disruption of ILC3 function is increasingly being demonstrated following infectious insult. Viral infections in particular are thought to disrupt tolerance and drive sensitization to dietary and microbial antigens in the intestine [
128]. Moreover, a dramatic loss of ILC3 and intestinal barrier integrity is observed in immunodeficiency virus infections of primates and humans (e.g., SIV, HIV) [
129‐
133]. HIV-1 infection in humans in particular is associated with impaired gut barrier and translocation of commensal bacteria which drive systemic inflammation [
134]. While profound depletion of infected CD4
+ T cells is the hallmark of HIV-1 infection, recent studies have demonstrated dysregulation of ILC3 in the blood, lymph, and/or intestinal tissues of HIV-1-infected humans or humanized mice and SIV-infected macaques [
130‐
133]. Thus, in the setting of HIV or SIV infection, loss of tissue-protective ILC3 responses may lead to loss of mucosal tolerance towards gut commensals, propagating intestinal and systemic inflammation. In support of this, loss of circulating ILC frequencies coincides with the elevation of markers associated with gut barrier breakdown and bacterial translocation [
130,
135]. In addition, SIV-infected macaques have reduced frequencies of small intestinal IL-17-producing ILCs following initial and persisting infection [
132]. Notably, ILC3 depletion in HIV/SIV infection does not appear to be due to direct viral infection [
130,
136]. Rather, mechanistic studies have suggested that ILC3 depletion is the result of apoptosis, possibly due to dysregulation of ILC survival signals [
137]. As such, analysis of ILC3 from humans with HIV-1 viremia shows upregulation of genes linked to apoptosis and cell death, including CD95 (Fas) [
130]. In humanized mice, CD95 expression on ILC3s can be induced by plasmacytoid DC-derived IFNα, which is also upregulated in the setting of HIV-1 infection [
133]. Thus, infection-induced cues likely impact upon ILC3 survival. Alternatively, loss or dysregulation of ILC3 responses may rather be a consequence of the depletion of CD4
+ T cells associated with HIV/SIV infection. As detailed above, ILC3 engage in multiple interactions with CD4
+ T cells and while the effect on T cells has been investigated in some detail, the consequences of these interactions for ILC3 remain unclear. In line with this possibility, absence of T cells has been associated with dysregulation of ILC3 function in the intestinal tissue [
138,
139], while
Tcra−/− mice exhibit a reduction in ILC3 numbers in the gut-draining mLN [
21]. Thus, it is tempting to speculate that HIV-induced depletion of T cells in infected patients may precipitate loss of ILC3s. Further work in this area may help delineate the nature of ILC3 and CD4
+ T cell interactions and increase understanding of how infection can result in a dramatic loss of ILC3 responses and precipitate inflammation in the intestine.
Moreover, it is likely viral infection may result in a loss of tolerance not only to commensal bacterial antigens but also to other environmental and dietary antigens (Fig.
2). For example, infection with reovirus has recently been demonstrated to drive sensitization to gluten and the development of celiac disease [
128]. Similarly, dysregulated ILC3 function and IL-22 secretion have been reported in celiac disease [
65,
140]; however, further work is needed to determine whether disruption of ILC3 responses is a common pathway in sensitization and inflammation against a wide range of microbial, environment, and dietary factors.