PD-1 expression on CD8+ T cells regulates their differentiation within lung allografts and is critical for tolerance induction

Abstract

Immunological requirements for rejection and tolerance induction differ between various organs. While memory CD8 T cells are considered a barrier to immunosuppression-mediated acceptance of most tissues and organs, tolerance induction after lung transplantation is critically dependent on central memory CD8 T lymphocytes. Here we demonstrate that costimulation blockade-mediated tolerance after lung transplantation is dependent on programmed cell death 1 (PD-1) expression on CD8 T cells. In the absence of PD-1 expression, CD8 T cells form prolonged interactions with graft-infiltrating CD11c cells; their differentiation is skewed towards an effector memory phenotype and grafts are rejected acutely. These findings extend the notion that requirements for tolerance induction after lung transplantation differ from other organs. Thus, immunosuppressive strategies for lung transplant recipients need to be tailored based on the unique immunological properties of this organ.

Deciphering the role of eosinophils in solid organ transplantation

“…Unlike most transplantable solid organs, lung alloimmune responses occur within the graft independent of secondary lymphoid tissue . Lungs also contain a large population of eosinophils, making them an ideal organ to investigate the role of this granulocyte in the alloimmune response.…”

“…Unlike most transplantable solid organs, lung alloimmune responses occur within the graft independent of secondary lymphoid tissue. [68][69][70] Lungs also contain a large population of eosinophils, making them an ideal organ to investigate the role of this granulocyte in the alloimmune response. Observational data have been interpreted to suggest that accumulation of tissue eosinophils is associated with acute lung allograft rejection.…”

Future prospects for CD8+ regulatory T cells in immune tolerance

“…66,72 Although IFNγ has proinflammatory consequences it has also been described as having pro-tolerogenic actions, through the production of molecules such as IDO, iNOs and FGL2. 68 IFNγ has been described as produced by several CD8 + Treg types 3,4,65,[73][74][75][76][77] although the function of IFNγ in CD8 + FOXP3 + cells has not been specifically analyzed. In contrast, and although suppression through IFNγ has been described by CD4 + Tregs in certain models 70,78 CD4 + FOXP3 + Tregs in general produce low levels of IFNγ.…”

An update on potentials and promises of T cell co‐signaling molecules in transplantation

“…Many of these co‐signaling molecules have key physiologic roles in immunological events such as T cell priming, clonal expansion, effector cell differentiation, immune response homeostasis, and peripheral tolerance. Definitive functions of regulatory molecules in distinct immunological events provide a platform for intervention in an almost specific effector function which seems the most critical such as humoral immunity or T effector memory (TEM) responses (O'Neill et al, ; Takahashi et al, ). For example, in the case of alloantibody production, specific inhibition of CD40/154 seems to benefit from a reasonable base.…”