title: The human alloreactive CD4+ T-cell repertoire is biased to a Th17 response and the frequency is inversely related to the number of HLA class II mismatches.
abstract: Estimates of precursor frequency and assessment of functional characteristics of alloreactive CD4+ T cells are all biased by the need for long-term culture. In this study, direct visualization of human alloreactive CD4+ T cells on the single-cell level was achieved using cell surface expression of CD154 as a tool for identification. The average frequency of alloreactive CD154+CD4+ T cells among peripheral blood CD4+ T cells was 0.1%, with half of the cells displaying a naive phenotype. The proliferation capacity and expression of cytokines after allogeneic stimulation resided in these CD154+CD4+ T cells. The repertoire of alloreactive CD4+ T cells was biased to a Th17 response, and on average 24% of alloreactive CD154+CD4+ memory T cells produced interleukin-17 (IL-17) after polyclonal stimulation. Unexpectedly, mixed cell cultures from human leukocyte antigen (HLA)-identical donors also generated alloreactive CD154+CD4+ T cells and yielded the highest frequency compared with HLA-nonidentical combinations. Therefore, reactivity to minor histocompatibility antigens between HLA-identical subjects appears to be relatively common. Alloreactive HLA-identical T cells did not proliferate or express cytokines, but were driven to proliferation in the presence of exogenous IL-2.
authors.affiliation: Department of Internal Medicine, Division of Nephrology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Nicolle H R
authors.initials: NH
authors.lastname: Litjens
authors.forename: Jacqueline
authors.initials: J
authors.lastname: van de Wetering
authors.forename: Nicole M
authors.initials: NM
authors.lastname: van Besouw
authors.forename: Michiel G H
authors.initials: MG
authors.lastname: Betjes
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001782:Blood Donors; D023201:CD40 Ligand; D049109:Cell Proliferation; D002478:Cells, Cultured; D006648:Histocompatibility / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D007376:Interleukin-2 / Q000494:pharmacology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D000949:Histocompatibility Antigens Class II; C508594:IL2 protein, human; D007376:Interleukin-2; D023201:CD40 Ligand