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Review
. 2017 Mar 2:8:195.
doi: 10.3389/fimmu.2017.00195. eCollection 2017.

Expansions of Cytotoxic CD4+CD28- T Cells Drive Excess Cardiovascular Mortality in Rheumatoid Arthritis and Other Chronic Inflammatory Conditions and Are Triggered by CMV Infection

Iain Broadley  1 , Alejandra Pera  2 , George Morrow  1 , Kevin A Davies  1 , Florian Kern  1
Affiliations
Review

Expansions of Cytotoxic CD4+CD28- T Cells Drive Excess Cardiovascular Mortality in Rheumatoid Arthritis and Other Chronic Inflammatory Conditions and Are Triggered by CMV Infection

Iain Broadley et al. Front Immunol. .

Abstract

A large proportion of cardiovascular (CV) pathology results from immune-mediated damage, including systemic inflammation and cellular proliferation, which cause a narrowing of the blood vessels. Expansions of cytotoxic CD4+ T cells characterized by loss of CD28 ("CD4+CD28- T cells" or "CD4+CD28null cells") are closely associated with cardiovascular disease (CVD), in particular coronary artery damage. Direct involvement of these cells in damaging the vasculature has been demonstrated repeatedly. Moreover, CD4+CD28- T cells are significantly increased in rheumatoid arthritis (RA) and other autoimmune conditions. It is striking that expansions of this subset beyond 1-2% occur exclusively in CMV-infected people. CMV infection itself is known to increase the severity of autoimmune diseases, in particular RA and has also been linked to increased vascular pathology. A review of the recent literature on immunological changes in CVD, RA, and CMV infection provides strong evidence that expansions of cytotoxic CD4+CD28- T cells in RA and other chronic inflammatory conditions are limited to CMV-infected patients and driven by CMV infection. They are likely to be responsible for the excess CV mortality observed in these situations. The CD4+CD28- phenotype convincingly links CMV infection to CV mortality based on a direct cellular-pathological mechanism rather than epidemiological association.

Keywords: CD4 T cells; autoimmune diseases; cardiovascular diseases; chronic inflammatory disease; cytotoxic T cells.

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Figures

Figure 1
Figure 1
T cell differentiation and the emergence of CMV-induced T cell phenotypes. Memory T cell differentiation is regulated by intracellular and extracellular factors. Mechanisms of memory development upon naïve T cell activation (antigen stimulation) are the subject of ongoing discussion. Since it has been reported that CD4+ T cell memory development resembles that of CD8+ T cells (34), we assumed that both T cell subsets follow similar pathways. However, transitional memory subsets sitting between central memory T cells (TCM) and effector memory T cells (TEM) have been described in the CD4+ T cell compartment. Several memory T cell subsets have been defined but their lineage relationship has remained unclear. Some models describe a linear origin of memory T cells directly from effector T cells; other models propose a divergent differentiation where naïve T cells give rise to memory and effector T cells through asymmetrical division. More recently a progressive differentiation pathway has been proposed, depending on stimulus intensity and duration (represented inside the box). According to this model, T cell fate depends on the duration of signaling and presence/absence of cytokines. Brief stimulation leads to the generation of TCM whereas sustained stimulation plus presence of cytokines generates TEM. Therefore, in the progressive model, a single naïve T cell will give rise to different memory T cell subsets that are the precursors of terminally differentiated effector T cells. Progression into these differentiated memory subsets relies on the gradual response to cytokines, acquisition of tissue homing receptors, resistance to apoptosis, and gain of effector functions while gradually losing lymph node homing receptors, proliferative capacity, and the ability to produce IL-2 production, to self-renew, and survive [for review, see Ref. (–39)]. Although the exact origin of the CD28− T cell phenotype is not clear, based on the literature, we hypothesize that these cells arise from terminally differentiated effector memory T cells (TEMRA) as well as TEM after exposure to CMV. Abbreviations: Th, T-helper cell; CTL, cytotoxic T cell; TSCM, stem cell memory T cell; TCM, central memory T cell; TEM, effector memory T cell; TEMRA, terminally differentiated (CD45RA reexpressing) effector memory T cell.
Figure 2
Figure 2
Proposed mechanisms for CMV-driven vascular damage. CMV-infected EC will downregulate MHC expression but produce non-infectious exosomes (NIE) loaded with CMV proteins, in particular UL55 (gB) (1) (68), allowing effective CMV antigen presentation by antigen-presenting cells (APC) following NIE uptake/processing. Vasculature-infiltrating CMV-specific CD4+ effector T cells will hence encounter these antigens on APC (shown as green CMV antigen in diagram; green block arrow) (2) and subsequently produce pro-inflammatory mediators such as IFN-γ. These induce the expression of fractalkine (FKN), IFN-γ-inducible protein 10, and possibly additional chemokines in EC (3) (69), which in turn attract infiltrating CD4+CD28− and probably also CD8+CD28− T cells to the ECs (4). These may be CMV-specific but possibly also non-CMV-specific (symbolized by red “target antigen” in diagram; red block arrow). They may kill ECs through perforin/granzyme secretion (5). Despite CMV infection, HLA-E expression remains unaffected in EC, so that interaction between HLA-E on EC and CD94/NKG2C on NK cells may also trigger CD94/NKG2C-mediated cytotoxicity (6) (71). NKG2C+ NK cells are known to be expanded by CMV infection and it is noteworthy that CD4+CD28− T cells may also express NKG2C (indicated by “?” in diagram). Acyclovir reduces CMV-specific T cell responses by inhibiting replication (72) and will probably reduce NIE formation in infected EC, thus reducing antigen presentation by APCs and subsequent effector T cell activation (7).
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