Expansion of CD45RA⁻FOXP3⁺⁺ regulatory T cells is associated with immune tolerance in patients with combined kidney and bone marrow transplantation

Abstract

Objectives Simultaneous transplantation of a solid organ and bone marrow from the same donor is a possible means of achieving transplant tolerance. Here, we attempted to identify biomarkers that indicate transplant tolerance for discontinuation of immunosuppressants in combined kidney and bone marrow transplantation (CKBMT). Methods Conventional kidney transplant (KT) recipients ( n = 20) and CKBMT recipients ( n = 6) were included in this study. We examined various immunological parameters by flow cytometry using peripheral blood mononuclear cells (PBMCs), including the frequency and phenotype of regulatory T (Treg) cell subpopulations. We also examined the suppressive activity of the Treg cell population in the setting of mixed lymphocyte reaction (MLR) with or without Treg cell depletion. Results Among six CKBMT recipients, three successfully discontinued immunosuppressants (tolerant group) and three could not (non‐tolerant group). The CD45RA − FOXP3 ++ Treg cell subpopulation was expanded in CKBMT recipients compared to conventional kidney transplant patients, and this was more obvious in the tolerant group than the non‐tolerant group. In addition, high suppressive activity of the Treg cell population was observed in the tolerant group. The ratio of CD45RA − FOXP3 ++ Treg cells to CD45RA − FOXP3 + cells indicated good discrimination between the tolerant and non‐tolerant groups. Conclusion Thus, our findings propose a biomarker that can distinguish CKBMT patients who achieve transplant tolerance and are eligible for discontinuation of immunosuppressants and may provide insight into tolerance mechanisms in CKBMT.

CPHEN‐016: Comprehensive phenotyping of human regulatory T cells

“…Several studies have revealed a decrease of activated Treg cells in human subjects with auto-immune disorders including rheumatoid arthritis (RA) and systematic lupus erythematosus (SLE) [16,17]. The activation status of human peripheral blood Treg cells can be further defined by the use of a combination of CD45RA and CCR7 to subdivide Tregs into four groups: Naïve (CCR7 + CD45RA + ), Central memory (CCR7 + CD45RA À ), effector memory (CCR7 À CD45RA À ) and TEMRA (CCR7 À CD45RA + ) (Figure 2C) [17][18][19]. An example of the utility of such clustering is its employment to define a specific CD45RA À CCR7À Treg cell subset with immunosuppressive properties in gastric cancer (Table 2) [17][18][19].…”

“…The activation status of human peripheral blood Treg cells can be further defined by the use of a combination of CD45RA and CCR7 to subdivide Tregs into four groups: Naïve (CCR7 + CD45RA + ), Central memory (CCR7 + CD45RA À ), effector memory (CCR7 À CD45RA À ) and TEMRA (CCR7 À CD45RA + ) (Figure 2C) [17][18][19]. An example of the utility of such clustering is its employment to define a specific CD45RA À CCR7À Treg cell subset with immunosuppressive properties in gastric cancer (Table 2) [17][18][19]. Treg subset named follicular regulatory T cells (Tfr) which was shown to suppress T follicular helper cells (TFH)-mediated antibody response [36].…”