Differential phenotypes of memory CD4 and CD8 T cells in the spleen and peripheral tissues following immunostimulatory therapy

Journal for ImmunoTherapy of Cancer

Annie Mirsoian¹  William J. Murphy¹  Christine M. Minnar¹  Gail D. Sckisel¹  Alexander D. Borowsky²  Jane Q. Chen²  Bruce R. Blazar³  Arta M. Monjazeb⁴  Marka Crittenden⁵  Brendan Curti⁵ 

[1] Department of Dermatology, University of California, Davis School of Medicine;Department of Pathology and Laboratory Medicine, Center for Comparative Medicine, University of California;Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, MMC 366 Mayo, 8366A;Department of Radiation Oncology, University of California, Davis School of Medicine, Comprehensive Cancer Center;Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center;

关键词: Immunotherapy;    Cancer;    PD-1;    Bystander Activation;    CD8;    NKG2D;   

DOI  :  10.1186/s40425-017-0235-4

来源: DOAJ

【 摘 要 】

Abstract Background Studies assessing immune parameters typically utilize human PBMCs or murine splenocytes to generate data that is interpreted as representative of immune status. Using splenocytes, we have shown memory CD4-T cells that expand following systemic immunostimulatory therapies undergo rapid IFNg-mediated activation induced cell death (AICD) resulting in a net loss of total CD4-T cells which correlates with elevated PD-1 expression. This is in contrast to CD8-T cells which expand with minimal PD-1 upregulation and apoptosis. In this study we expand upon our previous work by evaluating CD4 and CD8-T cell phenotype and distribution in peripheral organs which are more representative of immune responses occurring at metastatic sites following immunotherapy. Methods Phenotypic assessment of T cells in both lymphoid (spleen and LN) as well as peripheral organs (liver and lungs) in control and immunotherapy treated mice was performed to survey the impact of location on memory phenotype and activation marker status. Peripheral blood from patients undergoing systemic high dose IL-2 was also assessed for expression of PD-1 and memory phenotype. Results Here we reveal that, similar to what occurs in the spleen and lymph nodes, CD4-T cell numbers decreased while CD8-T cells expanded at these peripheral sites. In contrast to having differential expression of PD-1 as occurs in the spleen, both CD4 and CD8-T cells had significantly elevated levels of PD-1 in both the liver and lungs. Further analysis correlated PD-1 expression to CD62Llow (T effector/effector memory,TE/EM) expression which are more prevalent in CD4-T cells in general as well as CD8-T cells in peripheral organs. Similar elevated PD-1 expression on TE/EM cells was observed in patients undergoing systemic high-dose IL-2 therapy. Conclusions These data highlight PD-1 expressing and/or TE/EM subsets of T cells in circulation as more representative of cells at immune sites and underscore the importance of valuation both in lymphoid as well as target organs when making determinations about immune status. Trial registration ClinicalTrials.gov NCT01416831 . Registered August 12, 2011.

【 授权许可】

Unknown