Commensal Cryptosporidium colonization elicits a cDC1-dependent Th1 response that promotes intestinal homeostasis and limits other infections

Epithelial antigen presentation controls commensal-specific intraepithelial T-cells in the gut

“…Moreover, IFNγ production by T H 1 cells is completely dependent on the cDC1 population. In line with our observation, cDC1 were shown to control a T H 1 response to the recently discovered strain of Cryptosporidium that behaves as a commensal in WT mice (Russler-Germain et al ., 2021), suggesting that mechanisms described in our study may be widely used in response to intestinal microbes whose survival depends on tight association with IECs (Atarashi et al ., 2015; Chen and LaRusso, 2000)…”

“…Moreover, IFNγ production by TH1 cells is completely dependent on the cDC1 population. In line with our observation, cDC1 were shown to control a TH1 response to the recently discovered strain of Cryptosporidium that behaves as a commensal in WT mice (Russler-Germain et al, 2021), suggesting that mechanisms described in our study may be widely used in response to intestinal microbes whose survival depends on tight association with IECs (Atarashi et al, 2015;Chen and LaRusso, 2000) The tight association with the host´s IECs might even be the defining factor necessary for the induction of an immune response described here, that is based on MHCII expression on IECs coupled with induction of iIELs. Indeed, it was shown previously that while infection by another IEC-associated bacterium -the Citrobacter rodentium (Takahashi et al, 2021), is well tolerated in WT mice, a large fraction of their MHCII ΔIEC counterparts would not survive in the course of two weeks post infection (Jamwal et al, 2020).…”

“…Since T-cell responses are canonically driven by specific antigen presenting cells (APCs) populations, we next wanted to determine if SFB-induced IFNγ producing T-cells, responsible for the induction of MHCII on IECs are also regulated in such a way. Xcr1 + cDC1 were recently identified as the major inducers of T H 1 responses after intestinal infection by epithelial-adhesive cryptosporidium (Russler-Germain et al, 2021). To test whether cDC1 may also be involved in the SFB-mediated induction of MHCII + on IECs, we next utilized and analyzed SFB + Xcr1-Cre x R26-flox-STOP-flox-DTA (Xcr1-DTA) mice (Voehringer et al, 2008; Wohn et al, 2020), in which the mature cDC1 population is deleted by inducible diphtheria toxin expression (Figure S11A).…”

“…The control is based on MHCII navigation of the cytotoxic, bacterium-specific iIEL response which is able to increase the IECs turnover. This hypothesis is in line with reported observations since such a mechanism would be beneficial if the immune system fights invading pathogens (Jamwal et al ., 2020) or keeps in check commensal to prevent its overgrowth (Russler-Germain et al ., 2021). On the other hand, it could cause severe damage, when the immune system is targeting gut epithelial cells without discrimination (in a state of graft-versus-host disease) (Koyama et al ., 2019), or if the cytotoxic response to commensals gets out of control (like in inflammatory bowel disease) (Jamwal et al ., 2020; Tuganbaev et al ., 2020).…”

The Long and Short of Next Generation Sequencing for Cryptosporidium Research

“…In contrast, Russler-Germain et al. identified a strain of C. tyzzeri that occurs commensally in laboratory mice ( Russler-Germain et al., 2021 ). Genomic analysis of these variants (and others) may provide a genetic explanation for the observed differences in pathology.…”