Abstract
Infiltration of the lamina propria by inflammatory CD4+ T-cell populations is a key characteristic of chronic intestinal inflammation. Memory-phenotype CD4+ T-cell frequencies are increased in inflamed intestinal tissue of IBD patients compared to tissue of healthy controls and are associated with disease flares and a more complicated disease course. Therefore, a tightly controlled balance between regulatory and inflammatory CD4+ T-cell populations is crucial to prevent uncontrolled CD4+ T-cell responses and subsequent intestinal tissue damage. While at steady state, T-cells display mainly a regulatory phenotype, increased in Th1, Th2, Th9, Th17, and Th17.1 responses, and reduced Treg and Tr1 responses have all been suggested to play a role in IBD pathophysiology. However, it is highly unlikely that all these responses are altered in each individual patient. With the rapidly expanding plethora of therapeutic options to inhibit inflammatory T-cell responses and stimulate regulatory T-cell responses, a crucial need is emerging for a robust set of immunological assays to predict and monitor therapeutic success at an individual level. Consequently, it is crucial to differentiate dominant inflammatory and regulatory CD4+ T helper responses in patients and relate these to disease course and therapy response. In this review, we provide an overview of how intestinal CD4+ T-cell responses arise, discuss the main phenotypes of CD4+ T helper responses, and review how they are implicated in IBD.
Highlights
Up to 60% of lymphocytes residing in the intestinal tissue are cluster-of-differentiation 4 positive (CD4+ ) memory T-cells [1]
Patients with inflammatory bowel disease (IBD) develop uncontrolled inflammatory CD4+ T-cell responses which can be caused by either by insufficient suppression of inflammatory CD4+ T-cell responses and by insufficient host defense to pathogens, both resulting in tissue damage and chronic intestinal inflammation [3]
We describe how CD4+ memory T-cell responses arise, describe the functionally distinct CD4+ T-cell sub-populations and discuss how their function contributes to intestinal inflammation in IBD
Summary
Up to 60% of lymphocytes residing in the intestinal tissue are cluster-of-differentiation 4 positive (CD4+ ) memory T-cells [1]. Epithelial cells in the small intestine produce the chemokine CCL25, the ligand for CCR9, and lamina propria venules express the integrin α4β7 ligand mucosal vascular addressin cell adhesion molecule 1 (MADCAM1) [31,32,33]. Signals from the APC and MLN microenvironment determine the regionalization of the mucosally imprinted CD4+ T-cell response irrespective of the T-cell phenotype and function Both regulatory and inflammatory CD4+ T-cells are imprinted to home to the intestine. The majority of CD4+ T-cells in lamina propria harbor a CD38+ CD45ROCD44+ CD62Lneg effector memory phenotype [25,26,41,42]
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