BACKGROUND Follicular T-helper cells (Thf-cells) play a pivotal role in the differentiation of B-cells into Ig secreting cells, i.e. plasmablasts. CD4+CXCR5+ T-cells are their peripheral blood counterparts and share functional properties with Thf-cells. They comprise IFNΓ, IL17 and IL21 producing cells. B-cell mediated alloreactivity has been recognized as common cause of allograft dysfunction and predicts both early and late graft loss. Here we examined the frequency and functions of peripheral Thf-cells critical for B-cell activation before and after kidney transplantation (Tx).
METHODS Peripheral blood samples of patients (N=30) before and after kidney Tx and of healthy controls (N=16) were studied. Patients were treated with Tacrolimus, MMF and steroids. By flow cytometry the absolute numbers of CD4+CXCR5+ T-cells, and their cytokine producing profile (IL17, IL21 and IFNΓ) as well as the numbers of plasmablasts were measured. Functional interaction was studied by co-culture experiments (N=6) of sorted CD4+CXCR5+ and CD4+CXCR5- T-cells with endotoxin activated B-cells. B-cell differentiation and IgM and IgG production were determined in the presence and absence of Tacrolimus (10 ng/ml).
RESULTS Before Tx the absolute numbers of CD4+CXCR5+ T-cells were significantly lower than in healthy controls, and these numbers remained stable after Tx. However, after Tx IL21 and IFNΓ, but not IL17 production capacity by CD4+CXCR5+ T-cells was significantly reduced (both p<0.01). Moreover, patients had a significantly lower plasmablast count than healthy controls (p<0.02). Interestingly, after Tx a complete vanishing of plasmablasts was observed (p<0.0001). The co-cultures studies revealed that only CD4+CXCR5+ but not CD4+CXCR5- T-cells provided help to B-cell differentiation into Ig producing plasmablasts (p<0.05). This CXCR5+ dependent T-cell help to B-cells was completely inhibited by Tacrolimus. Differentiation of B-lymphocytes into plasmablasts was highly correlated with IgM and IgG production, Rs=0.91, p<0.0001 and Rs=0.85, p<0.0001, respectively.
CONCLUSION We showed that functionality of peripheral Thf-cells critical for the B-cell mediated immunity, is inhibited in kidney transplant patients. Moreover, Tacrolimus completely blocked B-cell differentiation into Ig secreting plasmablasts.
To cite this abstract in AMA style:Graav Gde, Dieterich M, Litjens N, Hesselink D, Betjes M, Weimar W, Bouamar R, Baan C. Disappearance of Immunoglobulin Producing Plasmablasts in Kidney Transplant Patients Is Associated with a Diminished Cytokine Producing Capacity by Peripheral Follicular T-Lymphocytes [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/disappearance-of-immunoglobulin-producing-plasmablasts-in-kidney-transplant-patients-is-associated-with-a-diminished-cytokine-producing-capacity-by-peripheral-follicular-t-lymphocytes/. Accessed April 9, 2020.
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