Functional Exhaustion of CD4(+) T Lymphocytes during Primary Cytomegalovirus Infection

Institute for Medical Immunology, Université Libre de Bruxelles, 6041 Charleroi, Belgium.
The Journal of Immunology (Impact Factor: 4.92). 08/2012; 189(5):2665-72. DOI: 10.4049/jimmunol.1101165
Source: PubMed


Human CMV establishes lifelong persistence after primary infection. Chronic CMV infection is associated with intermittent viral reactivation inducing high frequencies of CD4⁺ T lymphocytes with potent antiviral and helper properties. Primary CMV infection is characterized by an intense viral replication lasting for several months. The impact of this prolonged exposure to high Ag loads on the functionality of CD4⁺ T cells remains incompletely understood. In pregnant women with primary CMV infection, we observed that CMV-specific CD4⁺ T lymphocytes had a decreased capacity to proliferate and to produce IL-2. A very large proportion of CMV-specific CD4⁺ T cells had downregulated the expression of CD28, a costimulatory molecule centrally involved in the production of IL-2. Unexpectedly, both CD28⁻ and CD28⁺CD4⁺ T cells produced low levels of IL-2. This defective production of IL-2 was part of a larger downregulation of cytokine production. Indeed, CMV-specific CD4⁺ T cells produced lower amounts of IFN-γ and TNF-α and showed lower functional avidity during primary as compared with chronic infection. Increased programmed death-1 expression was observed in CD28⁺ CMV-specific CD4⁺ T cells, and programmed death-1 inhibition increased proliferative responses. These results indicate that primary CMV infection is associated with the exhaustion of CMV-specific CD4⁺ T cells displaying low functional avidity for viral Ags.

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    • "Similarly, Olson et al. reported that lower CD4+ naive cells were strongly associated with titers for CMV in humans [39]. Although there is some evidence in humans that CMV-specific CD4+ T cells can be involved in some antiviral responses, anti-viral immune responses are typically mediated by CD8+ T cells [40], [41]. Future studies examining CMV viral load in addition to antibody titers will help to clarify the impact of CMV on age-related lymphocyte changes of both CD4+ and CD8+ subtypes. "
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