Abstract
Follicular helper T cells (Tfh) are crucial for the production of high-affinity antibodies, such as alloantibodies, by providing the signals for B-cell proliferation and differentiation. Here, we demonstrate that human allogeneic dendritic cells (DC) stimulated with antibodies against HLA class II antigens preferentially differentiate human naive CD4+ T cells into Tfh cells. Following coculture with DCs treated with these antibodies, CD4+ T cells expressed CXCR5, ICOS, IL-21, Bcl-6 and phosphorylated STAT3. Blockade of IL-21 abrogated Bcl-6, while addition of the IL-12p40 subunit to the coculture increased CXCR5, Bcl-6, phosphorylated STAT3 and ICOS, indicating that they were both involved in Tfh polarization. We further phenotyped the peripheral T cells in a cohort of 55 kidney transplant recipients. Patients with anti-HLA-II donor-specific antibodies (DSA) presented higher blood counts of circulating Tfh cells than those with anti-HLA-I DSAs. Moreover, there was a predominance of lymphoid aggregates containing Tfh cells in biopsies from patients with antibody-mediated rejection and anti-HLA-II DSAs. Collectively, these data suggest that alloantibodies against HLA class II specifically promote the differentiation of naive T cells to Tfh cells following contact with DCs, a process that might appear in situ in human allografts and constitutes a therapeutic target.
Highlights
The premature graft loss can be due to various causes, including infection, nephrotoxicity or recurrence of the primary renal disease[1,2], alloimmunity remains the most common mechanism[2,3]
Antibodies against HLA class II stimulate monocyte-derived dendritic cells (DC) to mature into a CD80+CD86hi HLA-DR+BAFF+CCR7+ phenotype
The differentiation of monocyte-derived DCs (moDCs) into mature DCs with an APC phenotype predominantly occurred in the presence of antibodies against HLA class II (HLA-II-moDCs), as shown by the higher levels of CD80, CD86 and HLA-DR mean fluorescence intensity compared to unstimulated cells (Fig. 1A,B)
Summary
The premature graft loss can be due to various causes, including infection, nephrotoxicity or recurrence of the primary renal disease[1,2], alloimmunity remains the most common mechanism[2,3]. In biopsies with a high DC density, immunofluorescence and electron microscopy studies showed direct physical contact between DCs and T cells, and the DC density correlated with higher Ki-67-positive labeling indices in infiltrating T cells These observations suggest that the crosstalk between DCs and T cells may be driving an inflammatory response within the graft. The interaction between DCs and T cells in this context remains poorly understood Based on these observations, we hypothesized that one of the mechanisms by which antibodies against HLA class II lead to increased graft loss is by preferentially instructing naive T cells to differentiate into Tfh cells through their interaction with DCs. We show, in a human allogeneic in vitro model, that HLA class II-stimulated DCs polarize naive CD4+ T cells into a Tfh phenotype. We further demonstrate in a cohort of kidney transplant recipients that patients with DSAs against HLA class II have higher frequencies of circulating Tfh cells and a higher number of lymphoid aggregates containing Tfh cells in their allograft biopsies than those with antibodies against HLA class I
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