Commensal microbes drive intestinal inflammation by IL-17–producing CD4 ⁺ T cells through ICOSL and OX40L costimulation in the absence of B7-1 and B7-2

Abstract

The costimulatory B7-1 (CD80)/B7-2 (CD86) molecules, along with T-cell receptor stimulation, together facilitate T-cell activation. This explains why in vivo B7 costimulation neutralization efficiently silences a variety of human autoimmune disorders. Paradoxically, however, B7 blockade also potently moderates accumulation of immune-suppressive regulatory T cells (Tregs) essential for protection against multiorgan systemic autoimmunity. Here we show that B7 deprivation in mice overrides the necessity for Tregs in averting systemic autoimmunity and inflammation in extraintestinal tissues, whereas peripherally induced Tregs retained in the absence of B7 selectively mitigate intestinal inflammation caused by Th17 effector CD4 + T cells. The need for additional immune suppression in the intestine reflects commensal microbe-driven T-cell activation through the accessory costimulation molecules ICOSL and OX40L. Eradication of commensal enteric bacteria mitigates intestinal inflammation and IL-17 production triggered by Treg depletion in B7-deficient mice, whereas re-establishing intestinal colonization with Candida albicans primes expansion of Th17 cells with commensal specificity. Thus, neutralizing B7 costimulation uncovers an essential role for Tregs in selectively averting intestinal inflammation by Th17 CD4 + T cells with commensal microbe specificity.

IL-23 and IL-1β Drive Human Th17 Cell Differentiation and Metabolic Reprogramming in Absence of CD28 Costimulation

“…Furthermore, our data have determined that Th17 cells differentiated in absence of CD28 costimulation are responsive to restimulation rather than becoming anergic. ICOS and OX40L have been proposed as alternate costimulatory molecules to support Th17 differentiation (Paulos et al, 2010; Xin et al, 2014). We did not compare these in our study, as we found that stimulation with anti-CD3 and cytokines alone gave consistent Th17 responses, but it is possible there would be a further additive effect if these costimulatory molecules were present.…”

“…In our own hands, we have not found a consistent effect of CD28 costimulation on mouse Th17 cells. However, B7-deficient mice develop spontaneous colitis mediated by commensal-specific Th17 cells along with decreased T-reg cells (Xin et al, 2014), suggesting that, in mucosal sites in vivo , similar mechanisms of CD28-mediated Th17 regulation may occur.…”

“…B7 −/− mice have increased Th17 cell responses to gut commensal microbes, suggesting that CD28-B7 interactions may not be absolutely required for in vivo Th17 development (Xin et al, 2014). On the other hand, in vitro stimulation with agonistic anti-CD28 inhibited Th17 development from murine naive T cells, which was attributed to strongly increased IL-2 and interferon γ (IFNγ) (Bouguermouh et al, 2009).…”

Candida albicans Pathogenesis: Fitting within the Host-Microbe Damage Response Framework

“…Further, GI tract inflammation was shown to promote C. albicans colonization in chemically induced colitis in mice, which augments inflammatory responses via the PRR galectin-3 (116). C. albicans colonization also primed expansion of Th17 cells with commensal specificity, driving intes-tinal inflammation (117). Likewise, C. albicans colonization of the GI tract in germfree animals induced gastritis, demonstrating the inflammatory potential of this "benign" microbiota member (13).…”

Commensal Fungi Recapitulate the Protective Benefits of Intestinal Bacteria

“…The following day, the culture was washed and suspended in sterile saline. Antibiotic treated mice were administered an oral lavage of 10 6 fungal CFUs (in 30 µL phosphate-buffered saline) via P200 micropipette (Xin et al, 2014). …”