TCL1A, B Cell Regulation and Tolerance in Renal Transplantation.

François Brinas,Richard Danger,Sophie Brouard

doi:10.3390/cells10061367

François Brinas, Richard Danger + Show 1 more

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https://doi.org/10.3390/cells10061367

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Abstract

Despite much progress in the management of kidney transplantation, the need for life-long immunosuppressive therapies remains a major issue representing many risks for patients. Operational tolerance, defined as allograft acceptance without immunosuppression, has logically been subject to many investigations with the aim of a better understanding of post-transplantation mechanisms and potentially how it would be induced in patients. Among proposed biomarkers, T-cell Leukemia/Lymphoma protein 1A (TCL1A) has been observed as overexpressed in the peripheral blood of operational tolerant patients in several studies. TCL1A expression is restricted to early B cells, also increased in the blood of tolerant patients, and showing regulatory properties, notably through IL-10 secretion for some subsets. TCL1A has first been identified as an oncogene, overexpression of which is associated to the development of T and B cell cancer. TCL1A acts as a coactivator of the serine threonine kinase Akt and through other interactions favoring cell survival, growth, and proliferation. It has also been identified as interacting with others major actors involved in B cells differentiation and regulation, including IL-10 production. Herein, we reviewed known interactions and functions of TCL1A in B cells which could involve its potential role in the set up and maintenance of renal allograft tolerance.

Highlights

Transplantation has become the best treatment for end-stage renal disease.Continuous improvement in transplantation outcomes is due in part to better clinical management in the instauration of life-long immunosuppressive (IS) therapy, which is required to control recipients’ alloimmune response and prevent graft rejection [1]
As we shown later in the paper, T-cell Leukemia/Lymphoma protein 1A (TCL1A) expression is closely related to B cells, to early B cells before they move through germinal centers (GCs) [34,35]
Both BCR and CD40 stimulation induces CRTC2 cytoplasmic retention and TCL1A repression and increases cell apoptosis, whereas cAMP allowed translocation of CRTC2 to the nucleus, restored TCL1A expression and prevented the apoptosis of Ramos cells [85]. These results suggest that TCL1A expression relies heavily on BCR and CD40 stimulation, with its repression beginning in GC and relying to a certain extent on CRTC2 phosphorylation, with a signaling hierarchy that notably implicates cAMP

Summary

Introduction

Transplantation has become the best treatment for end-stage renal disease. Continuous improvement in transplantation outcomes is due in part to better clinical management in the instauration of life-long immunosuppressive (IS) therapy, which is required to control recipients’ alloimmune response and prevent graft rejection [1]. Blair et al characterized additional human Breg subsets They found that immature CD19+ CD24hi CD38hi transitional B cells in the peripheral blood of HVs showed the greatest ability to produce IL-10 following stimulation and were able to suppress T cell proliferation in coculture assays in an IL-10 level-dependent manner [42], which was confirmed in further studies [46,47]. This immature population corresponded to populations described in several studies as increased in blood obtained from kidney transplanted TOL patients [25,30,36,37]. How TCL1A is involved in B cell regulation and tolerance maintenance remain to be deciphered

TCL1A and B Cell Biology

TCL1A and B Cell Survival

Findings

Conclusions