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SAGE KE Bulletin Board

Marker for immune senescence – A short literature update

6 December 2005

Sven Koch, Graham Pawelec

Marker for immune senescence – A short literature update

Expression of killer cell lectin-like receptor G1 on antigen-specific human CD8+ T lymphocytes during active, latent, and resolved infection and its relation with CD57.

Ibegbu CC, Xu YX, Harris W, Maggio D, Miller JD, Kourtis AP.

J Immunol. 2005 May 15;174(10):6088-94.

The immune system is our most important defence against infection and possibly also cancer. Unfortunately it is progressively compromized with age. The elderly are more susceptible to infectious diseases, such as influenza and SARS, and, importantly, protective vaccination is less effective than in the young. An important component of the defences against viruses is the T cell system, consisting of CD4+ T-helper cells and CD8+ cytotoxic cells. From previous studies we know that both of these major subsets are detrimentally affected with increasing age (Pawelec et al.).

An infection with persistent viruses such as EBV or HCMV leads to clonal expansion and acquisition of marked immunological memory with highly specific CD8+ CTLs required to keep the lifelong infection under control. We and others have shown that very large numbers of these cells accumulate in the elderly and fill up the so-called immunological space, with the consequence that insufficient numbers of T cells specific for other infectious agents (or vaccines) are present (Ouyang et al.; Ouyang et al.; Khan et al.). These T cells mostly have an effector-memory phenotype but seem to be anergic. This impaired phenotype is closely associated with loss of CD28 expression and acquisition of inhibitory NK receptors, such as CD57 (HNK-1) or the Killer lectin-like receptor G1 (KLRG1). From previous studies we know that both of these receptors are markers for senescence and their expression patterns belong to the immune risk phenotype predicting mortality in the very elderly (Ouyang et al.; Brenchley et al.; Voehringer, Koschella, and Pircher).

A recent report from Ibegbu and colleagues focused on questions concerning the expression of these markers KLRG1 and CD57 and correlations with dysfunctional properties of different virus-specific T cells (Ibegbu et al.). Using tetramer technology, intracellular cytokine staining and multiparameter flow cytometry, they analysed KLRG1 expression on CD8+ T cells specific for CMV, EBV, HIV and Influenza. We and other groups have shown that KLRG1 is expressed by almost all CMV, EBV and HIV-specific CD8+ T cells, especially so in the elderly. In contrast, influenza-specific cells showed lower frequencies of KLRG1 expression because the virus is not persistent, with a latent state. Moreover, the group of JD Miller investigated coexpression and functional properties of CD57 and KLRG1. They found that CD57- KLRG1+ cells represent a CD27+, CD28+ CCR7+ CD127+ memory phenotype. In comparison, the CD57+ KLRG1+ cells belong to a CD27-, CD28-, CCR7- and CD127lo effector phenotype, which are terminally differentiated. The significant advance in this paper is that it was shown that this small CD57- KLRG1+ subset retains the ability to proliferate and secrete IFN-g trigged by specific antigen, whereas the CD57+ KLRG1+ cells possess no proliferative capacity and no IFN-g secretion, a hallmark of terminally differentiated senescent T cells, originally reported for all KLRG-1+ cells.

This new work therefore implies that CD57 and KLRG1 together represent an important marker for immune senescence and terminally differentiated cells. Thus, retention of functional CD57- KLRG-1+ cells while eliminating dysfunctional, anergic double-positive cells might offer an opportunity to increase immune responsiveness to vaccination in the elderly.

Reference List

Brenchley, J. M., et al. "Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ T cells." Blood 101.7 (2003): 2711-20.

Ibegbu, C. C., et al. "Expression of Killer Cell Lectin-Like Receptor G1 on Antigen-Specific Human CD8+ T Lymphocytes during Active, Latent, and Resolved Infection and its Relation with CD57." J.Immunol. 174.10 (2005): 6088-94.

Khan, N., et al. "Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals." J.Immunol. 169.4 (2002): 1984-92.

Ouyang, Q., et al. "Age-associated accumulation of CMV-specific CD8+ T cells expressing the inhibitory killer cell lectin-like receptor G1 (KLRG1)." Exp.Gerontol. 38.8 (2003): 911-20.

Ouyang, Q., et al. "Large numbers of dysfunctional CD8+ T lymphocytes bearing receptors for a single dominant CMV epitope in the very old." J.Clin.Immunol. 23.4 (2003): 247-57.

Ouyang, Q., et al. "Dysfunctional CMV-specific CD8(+) T cells accumulate in the elderly." Exp.Gerontol. 39.4 (2004): 607-13.

Pawelec, G., et al. "Human immunosenescence: is it infectious?" Immunol.Rev. 205 (2005): 257-68. Voehringer, D., M. Koschella, and H. Pircher. "Lack of proliferative capacity of human effector and memory T cells expressing killer cell lectinlike receptor G1 (KLRG1)." Blood 100.10 (2002): 3698-702.

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