Open Access Research article

Age-dependent changes in the expression of regulatory cell surface ligands in activated human T-cells

David H Canaday12*, Karen E Parker3, Htin Aung1, Hui Emily Chen2, Dariana Nunez-Medina2 and Christopher J Burant14

Author Affiliations

1 Geriatric Research Center Clinical Center (GRECC), Louis Stokes Cleveland VA, 10701 East Blvd., 44106 Cleveland, OH, USA

2 Division of Infectious Diseases and HIV Medicine, University Hospitals of Cleveland and Case Western Reserve University School of Medicine,10900 Euclid Ave, 44106 Cleveland, OH, USA

3 Department of Hospital Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA

4 Case Western Reserve University Frances Payne Bolton School of Nursing, Cleveland, USA

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BMC Immunology 2013, 14:45  doi:10.1186/1471-2172-14-45

Published: 1 October 2013



The immune system consists of multiple preformed and more specific adaptive immune responses, which are all subject to both positive and negative regulation. Programmed cell death protein 1 (PD-1) is a cell surface ligand implicated in the induction of anergy, Inducible T-cell Costimulator (ICOS) plays a stimulatory role in the development of both CD4+ and CD8+ T-cells, Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) plays a role in inhibitory regulation of T-cell activity, and T cell immunoglobulin and mucin protein 3 (Tim-3) has been described as a negative regulatory molecule in CD4+ helper type 1 cells and CD8+ cytotoxic type 1 cells. Each of these ligands is induced with T-cell activation allowing greater opportunity to have a regulatory role.


Flow cytometry was used to quantitate the expression of PD-1, ICOS, CTLA-4 and Tim-3 in human T-cells from geriatric and younger subjects both at baseline and after in vitro induction by mitogen. The magnitude of expression of the molecules increased significantly on activated blasts after mitogen stimulation compared to their baseline levels in resting cells. The increase in CTLA-4 expressing CD8+ T-cells was significantly higher after in vitro induction in older persons, while the increase in cells expressing Tim-3 and PD-1 was significantly reduced. In CD4+ T-cells, a greater increase in CTLA-4 expressing cells in older persons was the only difference between the age groups.


We found several significant changes in the older individuals in regulatory elements of the adaptive immune system that occur particularly after immune activation. These differences could have ramifications to autoimmunity as well as immunology against infection and tumors.

Immunosenescence; CD4; CD8; Adaptive immune system; Anergy; Co-receptor; PD-1; CTLA-4; ICOS; Tim-3