Regulatory T cells induce activation rather than suppression of human basophils

Abstract

Basophils are a rare granulocyte population that has been associated with allergic and inflammatory responses. It is essential to understand the regulatory mechanisms by which basophils are kept in check, considering the impact of dysregulated basophil function on immune responses under different pathological conditions. Among immunoregulatory cells, CD4CD25FoxP3 regulatory T cells (T) are the key players that maintain immune tolerance. The mechanisms by which T regulate and suppress diverse immune cell subsets have been studied extensively, but the impact of T on basophil functions is not well understood. We report that human basophils are refractory to T-mediated suppression and found that T stimulate resting basophils to induce the expression of activation markers including CD69, CD203c, and CD13 and the release of basophil cytokines including IL-13, IL-8, and IL-4. Mechanistically, T could induce human basophil activation via IL-3 and STAT5 activation, whereas cellular contact was dispensable. Inhibition of either IL-3-IL-3 receptor interactions or STAT5 phosphorylation abrogated T-mediated activation of basophils. These results provide evidence of direct positive effects that human T have on basophil activation and reveal a previously unrecognized feature of this cell subset well known for immunosuppressive functions.

Intravenous immunoglobulin induces IL-4 in human basophils by signaling through surface-bound IgE

“…In addition to IL-33, which is mainly produced by epithelial and endothelial cells, IL-3 secreted by activated T cells and mast cells is also known for inducing priming of basophils. 17,[33][34][35][36] We sought to confirm whether human basophil priming by IL-33 at a dose equivalent to that induced by IVIG in patients with rheumatic and neurologic autoimmune diseases 11,12 would stimulate IL-4 production, as proposed from mouse studies. IL-33 primed human basophils (based on CD69 expression) and induced IL-4, 37 but the extent of priming was only marginal when compared with IL-3mediated priming.…”

Natural Antibodies: from First-Line Defense Against Pathogens to Perpetual Immune Homeostasis

“…However, translation of these findings to humans failed to recapitulate the mechanisms although requirement of sialylation has been confirmed in other experimental models [78,79,82,83,88,89,92]. Studies in humans have revealed that IVIG can directly interact with basophils to induce IL-4 secretion, and can act either directly on Tregs or on DCs to expand Tregs [46,65,[93][94][95][96].…”

Therapeutic normal IgG intravenous immunoglobulin activates Wnt-β-catenin pathway in dendritic cells

“…By signaling via DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin), IVIG and its F (ab') 2 fragments induced prostaglandin E2 in human DCs by activating cyclooxygenase-2 pathway and mediated Treg expansion 26 . The IL-3-produced from these activated Tregs might license basophils to undergo activation by IVIG leading to the secretion of IL-4 and further suppression of effector Th17 and Th1 cells 56,66 . On the other hand, in the humanized DC-SIGN mice model, Fc fragments containing terminal α-(2,6) sialic acids interacted with DCs and induced IL-33 35 though in human, DC-SIGN-positive DCs failed to produce IL-33 upon exposure to IVIG 67 .…”