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

Gail D. Sckisel, Annie Mirsoian, Christine M. Minnar, Marka Crittenden, Brendan Curti, Jane Q. Chen, Bruce R. Blazar, Alexander D Borowsky, Arta M Monjazeb, William J Murphy

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number33
JournalJournal for ImmunoTherapy of Cancer
Volume5
Issue number1
DOIs
StatePublished - Apr 18 2017

Fingerprint

Spleen
T-Lymphocytes
Phenotype
Therapeutics
Immunotherapy
Interleukin-2
Lung
Liver
T-Lymphocyte Subsets
Cell Death
Up-Regulation
Cell Count
Lymph Nodes
Apoptosis

Keywords

  • Bystander activation
  • Cancer
  • CD8
  • Immunotherapy
  • NKG2D
  • PD-1

ASJC Scopus subject areas

  • Oncology
  • Immunology and Allergy
  • Cancer Research
  • Molecular Medicine
  • Pharmacology
  • Immunology

Cite this

Differential phenotypes of memory CD4 and CD8 T cells in the spleen and peripheral tissues following immunostimulatory therapy. / Sckisel, Gail D.; Mirsoian, Annie; Minnar, Christine M.; Crittenden, Marka; Curti, Brendan; Chen, Jane Q.; Blazar, Bruce R.; Borowsky, Alexander D; Monjazeb, Arta M; Murphy, William J.

In: Journal for ImmunoTherapy of Cancer, Vol. 5, No. 1, 33, 18.04.2017.

Research output: Contribution to journalArticle

Sckisel, Gail D. ; Mirsoian, Annie ; Minnar, Christine M. ; Crittenden, Marka ; Curti, Brendan ; Chen, Jane Q. ; Blazar, Bruce R. ; Borowsky, Alexander D ; Monjazeb, Arta M ; Murphy, William J. / Differential phenotypes of memory CD4 and CD8 T cells in the spleen and peripheral tissues following immunostimulatory therapy. In: Journal for ImmunoTherapy of Cancer. 2017 ; Vol. 5, No. 1.
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AU - Mirsoian, Annie

AU - Minnar, Christine M.

AU - Crittenden, Marka

AU - Curti, Brendan

AU - Chen, Jane Q.

AU - Blazar, Bruce R.

AU - Borowsky, Alexander D

AU - Monjazeb, Arta M

AU - Murphy, William J

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N2 - 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.

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KW - Cancer

KW - CD8

KW - Immunotherapy

KW - NKG2D

KW - PD-1

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