Poster 033 Follicle homing antigen presenting cells modulate TH2 bias: Conditional knockout of CXCR5 on CD11c+ cells prevents protective TH2 response following T. muris infection

The expression of the chemokine receptor CXCR5 by dendritic cells and their homing to B-cell follicles are suggested requirements for the generation of T-helper type 2 (TH2) cells in response to infection. Previous studies revealed that bone marrow chimeric mice deficient in CXCR5 in dendritic cells or CD4+ T-cells impaired the development of both T-follicular helper (TFH) or TH2 cells after infection with Heligmosomoides polygyrus (Leon, Ballesteros-Tato et al. 2012). Using a refined Cre/LoxP conditional gene expression model we have generated a specific CD11c-mediated CXCR5 knockout transgenic mouse on a C57Bl/ 6 genetic background. Characterisation of this model has revealed that CD11c+ cells are capable of trafficking to and are restricted within Tcell regions of lymph nodes & spleen, and are unable to traffic into the B-cell follicle. Infection with the gastrointestinal nematode Trichuris muris stimulates a TH2 dominated response in resistant mouse strains such as C57Bl/6 with worm clearance occuring within 21 days. Mouse strains susceptible to T. muris infection display a TH1 dominated response and remain persistently infected. We investigated the ability of CD11c-CXCR5-/- mice to mount an appropriate TH2 response to T. muris infection to facilitate clearance. Unlike CXCR5 fl control mice, CD11c-CXCR5-/- mice were unable to clear T. murisinfection after 30 days. Gene expression analysis of cytokine responses in the mesenteric lymph nodes of T. muris-infected mice revealed increased IFNG, IL1B, IL2, IL6, IL10 and reduced IL4, IL9 and IL25 mRNA expression in CD11c-CXCR5-/- mice compared to CXCR5 fl control mice. These alterations in cytokine expression were associated with increased expression of both IL-12 receptor beta subunits, IL12RB1 and IL12RB2, and the co-stimulatory molecules CD80 and CD86. We have demonstrated that CXCR5 deficiency in CD11c+ cells alters the ability to form a coherent TH2 type response to T. murisinfection, preventing worm clearance. These data confirm that for the efficient formation of a TH2 response to infection with intestinal nematodes, CD11c+ cells are required to localise to the B-cell follicle via expression of the chemokine receptor CXCR5. Leon, B., A. Ballesteros-Tato, et al. (2012). “Regulation of TH2 development by CXCR5+ dendritic cells and lymphotoxin-expressing B cells.” Nat Immunol 13(7): 681-690.