Functional Characteristics and Phenotypic Plasticity of CD57+PD1- CD4 T Cells and Their Relationship with Transplant Immunosuppression

J Immunol. 2021 Apr 1;206(7):1668-1676. doi: 10.4049/jimmunol.2000736. Epub 2021 Feb 17.


Costimulation blockade (CoB)-based immunosuppression offers the promise of improved transplantation outcomes with reduced drug toxicity. However, it is hampered by early acute rejections, mediated at least in part by differentiated, CoB-resistant T cells, such as CD57+PD1- CD4 T cells. In this study, we characterize these cells pretransplant, determine their fate posttransplant, and examine their proliferative capacity in vitro in humans. Our studies show that CD57+PD1- CD4 T cells are correlated with increasing age and CMV infection pretransplant, and persist for up to 1 y posttransplant. These cells are replication incompetent alone but proliferated in the presence of unsorted PBMCs in a contact-independent manner. When stimulated, cells sorted by CD57/PD1 status upregulate markers of activation with proliferation. Up to 85% of CD57+PD1- cells change expression of CD57/PD1 with stimulation, typically, upregulating PD1 and downregulating CD57. PD1 upregulation is accentuated in the presence of rapamycin but prevented by tacrolimus. These data support a general theory of CoB-resistant cells as Ag-experienced, costimulation-independent cells and suggest a mechanism for the synergy of belatacept and rapamycin, with increased expression of the activation marker PD1 potentiating exhaustion of CoB-resistant cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Abatacept / therapeutic use
  • Adult
  • CD4-Positive T-Lymphocytes / immunology*
  • CD57 Antigens / metabolism
  • Cell Plasticity
  • Cytomegalovirus / physiology*
  • Cytomegalovirus Infections / drug therapy
  • Cytomegalovirus Infections / immunology*
  • Drug Synergism
  • Female
  • Gene Expression Regulation
  • Graft Rejection / drug therapy
  • Graft Rejection / immunology*
  • Humans
  • Immunosuppression Therapy
  • Immunosuppressive Agents
  • Kidney Failure, Chronic / drug therapy
  • Kidney Failure, Chronic / surgery*
  • Kidney Transplantation*
  • Male
  • Middle Aged
  • Phenotype
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / metabolism*
  • Sirolimus / therapeutic use
  • Tacrolimus / therapeutic use


  • CD57 Antigens
  • Immunosuppressive Agents
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Abatacept
  • Sirolimus
  • Tacrolimus