Plaque T-cell activity: not so specific?

The notion that atherosclerosis has an inflammatory component was already proposed in the 19th century by Virchow, on the basis of light microscopic analysis of human plaques. The hypothesis was later supported by electron microscopic studies and was confirmed when immunohistochemical analysis revealed that the CD141 macrophage indeed was the major cell type in the plaque.1,2 More surprising was the finding that T lymphocytes were also present in substantial numbers in human plaques.1 The presence of cellular representatives of the specific, adaptive immune system in this disease has since then inspired a whole area of research, and our knowledge has certainly grown. T lymphocytes are designed to perform effector functions after activation by a specific antigen via the T-cell receptor. A first obvious question was, therefore, what these antigen-specific cells might be reactive to. Are there atherosclerosis-related antigens taking part in atherogenesis? This inquiry constitutes something of a “needle-in-a-haystack” problem, and the question of clonal composition is easier to address. The presence of clonal T-cell expansions would suggest reactivity to a limited number of antigens in early experimental atherosclerosis.3 More advanced human plaques, however, demonstrate a polyclonal T-cell composition.4,5 This characteristic does not constitute evidence that T cells are “nonspecific” (ie, are carrying reactivities not related to atherosclerosis), but it does suggest that no single antigen reactivity dominates the T-cell population. This result in itself is not surprising, because it is known from other inflammatory conditions, with known eliciting antigens, that antigen-specific cells in general constitute a minority of all infiltrating T cells. Furthermore, very few data support the concept of antigen-specific T-cell recruitment, suggesting instead that T-cell infiltrates arise by predominantly non–antigen-specific recruitment, which may be followed by local, clonal, antigen-driven proliferation. Indeed, several studies have by now demonstrated the presence of T cells in atherosclerotic plaques with specificity to atherosclerosis-related antigens, such as oxidized LDL,6 heat shock proteins,7 and Chlamydia pneumoniae.8 –10 Many studies in recent years have demonstrated pronounced effects on experimental atherosclerosis by immune system modulation, such as immunization or different approaches to immunosuppression.11–17 This in line with the current working hypothesis stating that antigenspecific T-cell activation is an important component of the atherosclerotic process.