Basophils control T-cell responses and limit disease activity in experimental murine colitis

Abstract

Basophils have been recognized as important inducers of T helper type 2 (Th2) responses. Using the colitis model of adoptive transfer of CD4 þ CD62L þ T cells into lymphopenic hosts, we have analyzed how basophils regulate T-cell responses and modulate disease activity. Transferred T cells rapidly proliferate, produce large amounts of interleukin (IL)-3, and expand the number of basophils in an IL-3-dependent manner. Depletion of basophils with two different antibodies substantially upregulated Th1 cytokines in transferred T cells at day 8. Increased Th1 cytokine expression persisted until the end of the experiment when basophil-depleted mice showed exacerbation of colitis with more severe loss of weight, histological damage, colonic leukocyte infiltration, and expression of pro-inflammatory cytokines. In vitro, we show that basophil-derived IL-4 and IL-6 downregulates expression of interferon-c, IL-2, and tumor necrosis factor in T cells. These data show a beneficial role of basophils in a T-cell driven model of autoimmunity.

Receptor activating NF-κB ligand (RANKL) is a constitutive intracellular protein in resting human basophils and is strongly induced on their surface by interleukin 3

“…To determine whether these in vitro findings hold true in vivo, it will be important to assess whether RANKL-expressing basophils could be identified in IL-3-rich inflammatory environments such as allergic tissues. In addition to allergic diseases, basophils have been shown to contribute to several disease states, such as autoimmunity and inflammatory disorders (Rodriguez Gomez et al 2014). For instance, Wakahara et al recently detected basophils in the mucosa of human Th17-associated lung and inflammatory bowel disease (Wakahara et al 2012).…”

“…Basophils were also shown to activate B cells and induce Ig production through their expression of the TNF superfamily members CD40L, BAFF and APRIL (Chen et al 2009;Gauchat et al 1993). Finally, murine basophils induced monocytes differentiation into M2 macrophages through releasing IL-4 in allergic skin lesions (Egawa et al 2013), and dampened pro-inflammatory Th1 cytokines induction during colitis (Rodriguez Gomez et al 2014). Although these data have yet to be confirmed in humans, a renewed interest on basophil immune functions has emerged from these studies, suggesting they could play non-redundant roles during adaptive immune responses and immunological disorders such as allergy and autoimmunity (Charles et al 2010).…”

Basophil Activation-Dependent Autoantibody and Interleukin-17 Production Exacerbate Systemic Lupus Erythematosus

“…Depletion of basophils in female MRL- lpr/lpr mice was performed by injection of 5 µg anti-mouse FcεRI (MAR1; eBioscience, San Diego, CA, USA) twice daily intraperitoneally for 3 days (18, 27), and control group (non-depleted) mice were treated with an isotype control antibody (eBioscience, San Diego, CA, USA). For basophil-adoptive-transfer, basophils were isolated from the peripheral blood of age-matched MRL- lpr/lpr mice using magnetic microbeads against CD49b + (Miltenyi Biotec GmbH, Germany), and FcεRI + and FcεRI ++ basophils were further isolated by FACS-sorting (Becton Dickinson, San Jose, CA, USA) (27) to yield a purity of greater than 90%.…”

New insights into basophil heterogeneity

“…Basophils have also been shown to infiltrate the intestines of patients with inflammatory bowel disease (IBD) [50]. As IBD is widely associated with alterations in gut commensal microbiota and T cell dysregulation, dysbiosis may be driving the increased basophil responses in IBD patients in addition to IL-3 released by activated T cells [51]. Likewise, basophils have been shown to be dysregulated in the setting of asthma in humans [52–55], and new evidence suggests that exposure to rhinovirus, one of the most common triggers of asthma exacerbation [56], causes basophils from atopic individuals to become more responsive to IgE cross-linking [57].…”