After binding its natural ligand cluster of differentiation 70 (CD70), CD27, a tumor necrosis factor receptor (TNFR)-associated factor-binding member of the TNFR family, regulates cellular activity in subsets of T, B, and natural killer cells as well as hematopoietic progenitor cells. In normal immune responses, CD27 signaling appears to be limited predominantly by the restricted expression of CD70, which is only transiently expressed by cells of the immune system upon activation. Studies performed in CD27-deficient and CD70-transgenic mice have defined a non-redundant role of this receptor-ligand pair in shaping adaptive T-cell responses. Moreover, adjuvant properties of CD70 have been exploited for the design of anti-cancer vaccines. However, continuous CD27-CD70 interactions may cause immune dysregulation and immunopathology in conditions of chronic immune activation such as during persistent virus infection and autoimmune disease. We conclude that optimal tuning of CD27-CD70 interaction is crucial for the regulation of the cellular immune response. We provide a detailed comparison of costimulation through CD27 with its closely related family members 4-1BB (CD137), CD30, herpes virus entry mediator, OX40 (CD134), and glucocorticoid-induced TNFR family-related gene, and we argue that these receptors do not have a unique function per se but that rather the timing, context, and intensity of these costimulatory signals determine the functional consequence of their activity.

Glucocorticoid-induced TNF receptor family-related protein (GITR) is expressed on activated and regulatory T cells, but its role on these functionally opposing cell types is not fully understood. Here we describe that transgenic expression of GITR’s unique ligand (GITRL) induces a prominent increase of both effector and regulatory CD4+ T cells, but not CD8+ T cells. Regulatory T cells from GITRL transgenic mice are phenotypically activated and retain their suppressive capacity. The accumulation of effector and regulatory T cells is not due to enhanced differentiation of naive T cells, but is a direct result of increased proliferation. Functional consequences of increased numbers of both regulatory and effector T cells were tested in an autoimmune model and show that GITR stimulation is protective, as it significantly delays disease induction. These data indicate that GITR regulates the balance between regulatory and effector CD4+ T cells by enhancing proliferation of both populations in parallel.

Chronic infection results in continuous formation and exhaustion of effector CD8 T cells and in failure of memory CD8 T cell development. Expression of CD70 and other molecules that provide costimulation to T cells is maintained during chronic infection. To analyze the impact of constitutive CD70-driven costimulation, we generated transgenic mice expressing CD70 specifically on T cells. We show that CD70 promoted accumulation of CD8 T cells with characteristics strikingly similar to exhausted effector CD8 T cells found during chronic infection. CD70 on T cells provided costimulation that enhanced primary CD8 T cell responses against influenza. In contrast, memory CD8 T cell maintenance and protection against secondary challenge with influenza was impaired. Interestingly, we found no effect on the formation of either effector or memory CD4 T cells. We conclude that constitutive expression of CD70 is sufficient to deregulate the CD8 T cell differentiation pathway of acute infection reminiscent of events in chronic infection.