Different regulatory and cytotoxic CD4⁺ T lymphocyte profiles in renal transplants with antibody-mediated chronic rejection or long-term good graft function

Comparative analysis of the different subsets of CD4⁺ T-lymphocytes may provide hints on the immunologic mechanisms operating in the long-term fate of a kidney transplant.We analyzed peripheral regulatory CD4⁺ T cells (Tregs) and CD4⁺ cytotoxic T lymphocytes (CTLs) in antibody-mediated chronic rejection (AMCR), in middle-term kidney transplants (2-4years, MTKT) with good graft function and rejection-free history, in long-term kidney transplants (>15years, LTKT) and in normal healthy subjects (NHS).Transplant groups with good prognosis (MTKT and LTKT) displayed a significant lower amount of CD4⁺CD25^high T lymphocytes than NHS, with a trend of a higher percentage in AMCR than in MTKT and LTKT. However, CD4⁺CD25^high Foxp3⁺ cells were significantly higher in LTKT and MTKT than AMCR. Characterization of CD4⁺CD25^high T cells showed a marked increase of intracellular CTLA-4 in the AMCR group in respect to the other transplant groups, while the expression of the surface molecule seemed to follow a reverse trend. In addition, CD27, a costimulatory receptor involved in long-term T cell survival and prevention of immune tolerance, is significantly reduced in CD4⁺CD25^high and CD4⁺Foxp3⁺ T cells in the LTKT in respect to the other transplant groups. CD4⁺CD25^highCD45RO⁺ and CD4⁺Foxp3⁺CD45RO⁺ regulatory T cells with memory function were increased in LTKT compared to NHS and for the latter also in AMCR group.Finally, CD4⁺CTLs that were quantified on the basis of granzyme A expression, were more represented in AMCR patients in comparison to the other groups. Strikingly, CD27 in the CD4⁺CTLs was suppressed in LTKT and MTKT and markedly expressed in AMCR group. No significant differences in the expression of CD28 were observed among different groups.In conclusion, different profiles of Tregs and CD4⁺CTL populations correlate with different long-term conditions of kidney-transplanted patients, suggesting their role in the development of immunologic events in kidney transplantation.