Eomesoderminlo CTLA4hi Alloreactive CD8+ Memory T Cells Are Associated With Prolonged Renal Transplant Survival Induced by Regulatory Dendritic Cell Infusion in CTLA4 Immunoglobulin–Treated Nonhuman Primates

Abstract

Background Memory T cells (Tmem), particularly those resistant to costimulation blockade (CB), are a major barrier to transplant tolerance. The transcription factor Eomesodermin (Eomes) is critical for Tmem development and maintenance, but its expression by alloactivated T cells has not been examined in non-human primates. Methods We evaluated Eomes and co-inhibitory cytotoxic T lymphocyte antigen-4 (CTLA4) expression by alloactivated rhesus monkey T cells in the presence of CTLA4 immunoglobulin (Ig), both in vitro and in renal allograft recipients treated with CTLA4Ig, with or without regulatory dendritic cell (DCreg) infusion. Results In normal monkeys, CD8+ T cells expressed significantly more Eomes than CD4+T cells. By contrast, CD8+T cells displayed minimal CTLA4. Among T cell subsets, central Tmem (Tcm) expressed the highest levels of Eomes. Notably, EomesloCTLA4hi cells displayed higher levels of CD25 and Foxp3 than EomeshiCTLA4lo CD8+ T cells. Following allostimulation, distinct proliferating EomesloCTLA4hi and EomeshiCTLA4lo CD8+ T cell populations were identified, with a high proportion of Tcm being EomesloCTLA4hi. CB with CTLA4Ig during allostimulation of CD8+T cells reduced CTLA4 but not Eomes expression, significantly reducing EomesloCTLA4hi cells. After transplantation with CB and rapamycin, donor-reactive EomesloCTLA4hi CD8+T cells were reduced. However, in monkeys also given DCreg, absolute numbers of these cells were elevated significantly. Conclusions Low Eomes and high CTLA4 expression by donor-reactive CD8+ Tmem is associated with prolonged renal allograft survival induced by DCreg infusion in CTLA4Ig-treated monkeys. Prolonged allograft survival associated with DCreg infusion may be related to maintenance of donor-reactive EomesloCTLA4hi Tcm.

Tolerogenic Dendritic Cells: The Pearl of Immunotherapy in Organ Transplantation

“…α1-Antitrypsin-pulsed DC are characterized by decreased expression of MHC-II, CD80, and CD86 and high expression of IDO. After transferring these IDO + Tol-DC, the kidney allograft survival period is prolonged and Treg increase ( 87 ). Human soluble CD83 (hsCD83) is able to inhibit DC maturation and cause the anergy of Teff.…”

“…Eomesodermin (Eomes), a key transcription factor in CD8 + Tmem ( 149 ), play a critical role in long-term survival of antigen-specific central Tmem. The prolonged survival of renal allografts after both CTAL4Ig and donor-derived Tol-DC therapy might be related to the maintenance of donor-reactive Eomes low CTLA4 high central Tmem, which displayed a regulatory phenotype in vivo ( 87 ). Compared to CNI, CTLA4Ig may preserve renal function and improve long-term outcomes in kidney transplantation ( 150 ).…”

Renal Allograft Survival in Nonhuman Primates Infused With Donor Antigen-Pulsed Autologous Regulatory Dendritic Cells

“…We have also reported that prolonged renal allograft survival in monkeys given donor‐derived DCreg is associated with an increased incidence of donor‐reactive CTLA4 hi CD8 + T cells expressing low levels of the memory cell survival factor Eomesodermin (Eomes) posttransplant. In monkeys given either no or unpulsed autologous DCreg, the incidence of donor‐reactive Eomes lo CTLA4 hi CD8 + T cells was reduced significantly 4 weeks posttransplant (median = 8.1%) compared to pretransplant (median = 16.6%) (p < 0.05), whereas in monkeys given Ag‐pulsed autologous DCreg, the incidence of this subset was increased posttransplant (median = 8.1%) compared to pretransplant (median = 5.5%) (Figure B).…”

Impact of infection on transplantation tolerance

“…During an innate immune response, DCs can sense pathogen derived molecular patterns (PAMPs) via pattern-recognition receptors (PRRs), and activate downstream inflammatory immune responses. [73][74][75][76][77][78][79][80][81] First of all, downregulation of MHC-II and costimulatory molecules impair their antigen presenting ability, promoting hypo-responsiveness of cognate alloreactive T cells. However, the presence of an innate immune response may alter the phenotype and function of DCs by promoting their activation F I G U R E 2 Effects of infection on the regulatory immune cell network.…”

“…72 Their tolerogenic efficacy in transplantation and mechanisms of action has been well-described in rodent and non-human primate (NHP) transplant models. [73][74][75][76][77][78][79][80][81] First of all, downregulation of MHC-II and costimulatory molecules impair their antigen presenting ability, promoting hypo-responsiveness of cognate alloreactive T cells. Second, Tol-DCs can induce apoptosis of both naive and memory T cells through activation of Fas/FasL pathway and upregulation of IDO.…”