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The influence of cytomegalovirus carrier status on lymphocyte subsets and natural immunity was noticed since the late eighties (Gratama et al., 1987). In this context there are several studies that confirm the importance of CD8+ T cells in controlling CMV disease, particularly in primary infection. For instance, subsets of CD8+, CD57+ cells in normal, healthy individuals were found to correlate positively with human CMV carrier status, phenotypic and functional analyses (Wang et al., 1993, Wang and Borysiewicz, 1995). Furthermore, Sester and colleagues demonstrated that during primary infection, the cellular immune response is mainly dominated by CMV-specific CD8+ T cells (Sester et al., 2002b). This was also established by Reusser’s group, who showed that the delay in restoration of CMV-specific CD8+ T cells after bone marrow transplantation (BMT) increased therisk of developing severe CMV disease (Reusser et al., 1991). Furthermore, transfer of CMV-specific CD8+ T cellclones derived from the donor bone marrow led to improvement in outcome with regards to CMV infection in recipients (Walter et al., 1995).

In recent years, there has been an increasing literature on the role of CD4+ T cells in controlling CMV infection. For instance, studying the characteristics of CMV-specific CD4+ and CD8+ T cells during primary CMV infection in renal transplant recipients demonstrated that formation of CD8+ T cells alone was not sufficient for controlling infection; effector memory CD4+ T cells were shown to be essential for recovery of CMV infection (Gamadia et al., 2003). This is also true in the case of BMT patients, where reconstitution of cellular immunity against CMV required both CMV-specific CD8+ and CD4+ T cells (Walter et al., 1995). Further evidence of the importance of

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CD4+ T cells in defence against CMV is the ability of CMV-stimulated CD4 cells (from CMV-seropositive but not CMV-seronegative donors) to suppress CMV gene expression in CMV encephalitis (Cheeran et al., 2000).

It is believed that the chief function of CD4+ T cells is to give help to CMV-specific CD8+ T cells, particularly in maintaining the memory response. The initial suggestion that CD4+ T cells are playing this important role comes from the observation that cytotoxic CD8+ T cell activity declined in patients deficient in CD4+ T-helper cells specific for CMV, which indicates that CD4+ helper cell function is essential for the persistence of CD8+ T cells (Walter et al., 1995). However, the murine model of CMV infection suggests this role is only important during the primary phase of infection; in other words, the depletion of CD4+ T cells during recall responses has minimal or no effect on the memory CD8+ T cell response, meanwhile depletion during the priming phase (acute stage) is associated with a remarkable reduction in responses by memory CD8+ T cells to re-infection (Shedlock and Shen, 2003).

Besides giving help to CD8+ T cells, CD4+ T cells can directly kill CMV-infected cells. It is proposed that in primary CMV infection, cytotoxic CD4+ T cells appear after cessation of the viral load. These cells are characterized by a loss of CD27 and loss of CD28, and upregulation of CD57, which indicates an advanced stage of cellular differentiation. They also have cytolytic molecules such as granzyme B and perforin, which might be used in killing of CMV-infected cells (Appay, 2004). The triggering of killing potential of these CD4+ T cells can be via direct recognition of endogenous antigen in addition to exogenous antigens (the normal pathway for CD4+ T cell activation), as shown by studies of the CMV-gB protein, which is processed and

expressed efficiently by MHC-II of the infected cells (Hegde et al., 2005). Although the response of CD4+ T cells can be demonstrated against a wide range of CMV antigens, the main responses are found to be against pp65 and glycoprotein B, which are also strong antigens for CD8+ T cells. IE1, though a strong antigen for CD8+ T cells, is less stimulatory than pp65 and gB for CD4+ T cells (Sylwester et al., 2005). This may be because IE-1 does not access the class II processing pathway as readily as pp65 and gB, which are both structural components of the virus particle and more classical exogenous antigens.

Furthermore, Casazza et al showed that acquisition of direct antiviral effector functions by pp65-specific CD4+ T cells with cellular maturation (Casazza et al., 2006). This included acquiring a highly differentiated effector memory phenotype, that was characterized by the relatively low frequency of IL-2–producing CD4+ T cells compared with IFN-γ, TNF-α, and MIP-1β production. Indeed, this suggests that the primary role of CMV pp65-specific CD4+ T cells during chronic infection is not solely one of supplying CD4+ T cell help.

Although it seems that the cooperation between NK cells on one hand, and B cells and αβ T cells on the other hand are sufficient to prevent most infections, γδ T cell deficiency is found to be associated with immune deficiency (Chung et al., 2006). Besides that, a remarkable expansion of γδ T cells can be demonstrated during bacterial as well as some viral and parasitic infestation. For instance, γδ T cell proportions increase considerably following infection with intracellular pathogens such as Mycobacterium tuberculosis (Janis et al., 1989), influenza (Carding et al., 1990),

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Furthermore, clinical studies in transplant recipients showed that CMV infection resolves better when circulating γδ T cells expand (Dechanet et al., 1999b). Based on these and other observations that indicate the presence of interaction between different T cell subsets (Vincent et al., 1996), there is a strong belief that γδ T cells play a very important role in immune pathology of infectious disease including CMV infection. The percentage of Vδ2neg γδ T cells in peripheral blood has ben shown to remarkably increase in renal transplant patients with active CMV infection (Dechanet et al., 1999b). Moreover, the resolution of CMV viremia was found to be directly proportionate to the expansion of the Vδ2neg γδ T cell population (Lafarge et al., 2001). Indeed, these observations strongly indicate the important role of Vδ2neg γδ T cells in combating CMV infection. Supporting this proposal, Halary and colleagues generated γδ T cell clones from renal transplant patients (Halary et al., 2005). They demonstrated that Vδ2neg γδ T cells specifically react with CMV-infected cells by producing the pro-inflammatory cytokine, tumour necrosis factor –α (TNFα).

1.2.7 Influence of CMV chronic infection on the immune system of elderly