Distinct regulation of adaptive and innate immune responses by Candida albicans

Introduction & aims: Candida albicans (C. alb) is a fungal commensal of the GI tract. The surface of C. alb is composed mostly of glycans and their improper recognition is speculated as a trigger of chronic inflammation. Indeed, antibodies against surface glycans such as ASCA and ALCA are elevated in IBD. We hypothesized that glycans from C. alb modulate immune responses. Thus, our aim was to examine the effect of C. alb on T cell and intestinal epithelial cell (IECs) function and compare it to synthetic glycans.

Methods & results: Exposure of naive PBMCs to heat killed C. alb yeast or hyphae activated T cells (determined by CD25 and CD69 staining) and increased pro-inflammatory IL17 secretion (ELISA). However, C. alb did not modulate T cell proliferation (MTT incorporation) or apoptosis (Annexin-V). In contrast, exposure of CD3-stimulated PBMCs to C. alb restricted activation, proliferation, IL17 secretion, and apoptosis. Synthetic glycans (zymosan, mannan, Pam3CSK, or laminarin) did not influence PBMC function. Last, we observed no differences between IBD and control T cells in their response to C. alb.

In IECs (Caco2), co-culture with either hyphae or yeast C. alb up-regulated expression of TLR2, -4, E-cadherin, CXCR1, and evoked secretion of IL6 and TSLP. A similar pattern was observed with β-glucans (laminarin and Pam3CSK) stimulation, but not with other glycans (mannan and zymosan). Interestingly, when we examined the effect of C. alb on IEC wound healing, hyphae, but not the yeast form of C. alb, enhanced IEC migration over the wound edge.

Conclusion: In T cells, hyphae and yeast operate similarly, but influence differenzially resting and stimulated T cells. Also, glycans are not mimicking these effects, suggesting a different mode of action. We deduce differenzial pathway of C. alb infection in IBD, as no differences were observed between IBD and normal PBMCs. In IECs, yeast and hyphae provoke different biological effects in respect to wound healing, implying that both forms of fungi have distinct biological influence within the GI tract. Our studies show that cells of both the innate and adaptive immune system exert different biological functions in response to C. alb, paving the path to further explore the biological role of fungi in mucosal inflammation.