Dendritic Cell-T-Cell Circuitry in Health and Changes in Inflammatory Bowel Disease and Its Treatment

Abstract

Background: Dendritic, antigen-presenting cells (DCs) determine not only whether lymphocytes produce different types of immune response but also tissue-homing profiles of lymphocytes they stimulate. For example, in health, mucosal DC stimulate T cells focused to home to the mucosa; DC/T-cell circuitry thus targets immune responses to specific tissue locations. Therapies being introduced for inflammatory bowel disease (IBD) include antibodies to gut-homing molecules such as α4β7 (Vedolizumab) used ostensibly to block gut-homing lymphocytes. However, such lymphocytes are dependent on the tissue specificity of DC that stimulated them. Key Messages: In health, blood DCs have the potential to home to multiple tissues including gut (α4β7+) and skin (CLA+). DCs have become gut-specific within the intestinal microenvironment stimulated partially by local retinoid to express α4β7 (mucosal homing marker) and/or CCR9 (ileal homing marker) in the absence of skin-specific indicators. They spread veiled extensions, sample their environment, acquire/process antigens, produce cytokines and initiate innate immunity. Myeloid DC also traffic to draining lymph nodes where compartmentalization of adaptive immune responses is determined by DCs from the site of antigen exposure which dictate the homing profiles of lymphocytes they stimulate. In IBD, site and activity of disease are reflected in changes in homing/activation of gut DCs and T-cells they stimulate and also, in greater gut specificity and activation of blood DC. Homing potential of DC can be modulated toward mucosa or skin by vitamins A and D, respectively. Infliximab or interleukin-6 can divert homing profiles toward skin, perhaps predisposing to skin involvement in IBD. Probiotic bacteria or their products can also change homing profiles of gut DC toward skin homing and away from gut. Conclusions: In conclusion, development of gut focused inflammation and its treatment relies on changes in DC tissue specificity; therefore, removal or diversion of gut-homing DC as well as T-cells is likely to be critical in prevention of gut-focused inflammation in IBD.