doi: 10.1161/01.ATV.0000254856.95617.38
© 2007 American Heart Association, Inc.
Letters to the Editor |
Letter to the Editor
Autoreactive CD4+CD28– T Cells and Acute Coronary Syndromes
Department of Cardiac and Vascular Sciences, St. George’s University of London, UK
To the Editor:
The review article by Robertson and Hansson1 on the role of T cells in atherogenesis is comprehensive and scholarly. A particular aspect of the problem, however, which in our view is of potential pathogenic relevance, has been only tangentially addressed in the article. Robertson and Hansson1 mention that patients with acute coronary syndrome (ACS) may exhibit a peripheral burst of an unusual and aggressive CD4+ T cell subset that lacks the expression of the CD28 receptor (CD4+CD28– cells). In these patients, CD4+CD28– cells can represent up to 50% of the circulating CD4+ cell compartment, and are also preferentially recruited into culprit lesions.2,3 CD4+CD28– T cells, unlike typical CD4+cells, produce high levels of interferon (INF) (INF)-
, interleukin (IL)-2, and cytotoxic perforin granules.3 The potent proinflammatory and cytolytic properties of these T cells are considered to be important factors contributing to atheromatous plaque destabilization.4,5
Robertson and Hansson1 suggest that the cytolytic function of CD4+CD28– cells against autologous cells may be nonspecific and therefore indiscriminate. Published data, however, indicate that this may not be the case, as the loss of CD28 cell surface expression and clonal outgrowth of these T cells is reported to be the result of their chronic exposure to a restricted spectrum of antigens,6,7 which may be present in the atherosclerotic plaque and/or the peripheral circulation.3 Indeed, we have recently shown that circulating CD4+CD28– cells in ACS patients are activated in response to a restricted antigenic stimulation.8 CD4+CD28– cells from >50% of our patients reacted specifically to human heat shock protein 60 (hHSP60) releasing high levels of INF- and perforin.8 We have also shown that hHSP60 presentation by target cells was a prerequisite for activation of CD4+CD28– in at least a proportion of ACS patients.8 The association between HSP60 and atherogenesis is of interest, as discussed by Robertson and Hansson,1 as hHSP60 is expressed in vulnerable atheromatous lesions and its expression correlates with the progression of atherosclerosis.9–11 A correlation between high levels of circulating hHSP60 and the presence of hHSP60-reactive CD4+CD28– cells has been demonstrated in ACS patients.8
The cytolytic capability of CD4+CD28– cells is thought to play an important role in plaque rupture and ACS.3 In this context, a previous report showed that C-reactive protein, at concentrations frequently found in patients at risk of coronary events, enhanced lysis of endothelial cells by CD4+CD28– T cells in redirected cytotoxicity assays.5 Therefore, sensitization of endothelial cells by acute phase proteins to the cytotoxic process can aggravate hHSP60-mediated endothelial cell injury by CD4+CD28– cells and further contribute to plaque vulnerability.
Finally, while chronic antigen stimulation is considered to be responsible for the emergence of CD4+CD28– cells in ACS, cytokines are also reported to be involved in the peripheral expansion and lesion recruitment of these cells. The role of IL-12 in enhancing the tissue recruitment of CD4+CD28– cells is discussed by Robertson and Hansson;1 however, the upregulatory effect of this cytokine on CD28 expression by these T cells is of importance, and should be highlighted.12 Interestingly, the effect of IL-12 is counteracted by tumor necrosis factor (TNF)-
, which has been shown to downregulate the expression of this receptor and favor the expansion of CD4+CD28– cells.13 Recent studies have shown that selective TNF- blockade reduced the number of peripheral CD4+CD28– cells in patients with ACS and rheumatoid arthritis.14–16 Regulatory mechanisms operative in CD4+CD28– T cells are intriguing and require further investigation.
Acknowledgments
Disclosures
None.
References
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