title: TIGIT-positive circulating follicular helper T cells display robust B-cell help functions: potential role in sickle cell alloimmunization.
abstract: 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-stimulatory 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 the differentiation of B cells 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 tyro-sine-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 immunoglobulin G production. These findings open the way to defining new diagnostic and therapeutic strategies in modulating humoral responses in alloimmunization, and possibly vaccination, autoimmunity and immune deficiencies.
authors.affiliation: Laboratory of Complement Biology, New York Blood Center, NY, USA.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Godefroy
authors.affiliation: Laboratory of Complement Biology, New York Blood Center, NY, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhong
authors.affiliation: Laboratory of Flow Cytometry, New York Blood Center, NY, USA.
authors.forename: Petra
authors.initials: P
authors.lastname: Pham
authors.affiliation: Departments of Pediatrics and Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Friedman
authors.affiliation: Laboratory of Complement Biology, New York Blood Center, NY, USA kyazdanbakhsh@nybloodcenter.org.
authors.forename: Karina
authors.initials: K
authors.lastname: Yazdanbakhsh
mesh_terms: D000293:Adolescent; D000755:Anemia, Sickle Cell / Q000097:blood / Q000276:immunology* / Q000628:therapy; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology*; D007518:Isoantibodies / Q000097:blood / Q000276:immunology; D008297:Male; D011971:Receptors, Immunologic / Q000276:immunology* / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism; D065227:Transfusion Reaction
chemical_list: D007074:Immunoglobulin G; D007518:Isoantibodies; D011971:Receptors, Immunologic; C534712:TIGIT protein, human