T follicular helper cells are the main CD4+ T cells specialized in supporting B cell responses, but their role in driving transfusion-associated alloimmunization is not fully characterized. Reports of T follicular helper subsets displaying various markers and functional activities underscore the need for better characterization/identification of markers with defined functions. Here we show that a previously unidentified subset of human circulating T follicular helper cells expressing TIGIT, the T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory domains, exhibit strong B cell help functions. Compared to the subset lacking the receptor, T follicular helper cells expressing this receptor up-regulated co-stimulation molecules and produced higher levels of interleukins (IL-21 and IL-4) critical for promoting B cell activation/differentiation. Furthermore, this subset was more efficient at inducing B cell differentiation into plasmablasts and promoting immunoglobulin G production. Blocking antibodies abrogated the B cell help properties of receptor expressing T follicular helper cells, consistent with the key role of this molecule in T follicular helper-associated responses. Importantly, in chronically transfused patients with sickle cell anemia, we identified functional differences of this subset between alloimmunized and non-alloimmunized patients. Altogether, these studies suggest that expression of the T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory domains not only represents a novel circulating T follicular helper biomarker, but is also functional and promotes strong B cell help and ensuing IgG production. These findings open the way to defining new diagnostic and therapeutic strategies in modulating humoral responses in alloimmunization, and possibly vaccination, autoimmunity or immune deficiencies.
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