Distinct roles of CD4+ T cell subpopulations in retroviral immunity: lessons from the Friend virus mouse model

Abstract

It is well established that CD4(+) T cells play an important role in immunity to infections with retroviruses such as HIV. However, in recent years CD4(+) T cells have been subdivided into several distinct populations that are differentially regulated and perform widely varying functions. Thus, it is important to delineate the separate roles of these subsets, which range from direct antiviral activities to potent immunosuppression. In this review, we discuss contributions from the major CD4(+) T cell subpopulations to retroviral immunity. Fundamental concepts obtained from studies on numerous viral infections are presented along with a more detailed analysis of studies on murine Friend virus. The relevance of these studies to HIV immunology and immunotherapy is reviewed.

Figure 1

Distinct populations of CD4⁺ T cells regulate the virus-specific immune response during acute Friend Retrovirus infection. CD4⁺ helper T cells and follicular helper T cells augment virus-specific cytotoxic T cell and antibody responses. In addition, a subpopulation of effector CD4⁺ T cells directly inhibits virus replication. However, at the same time natural regulatory T cells expand and start to suppress effector T cell responses, which interferes with control of virus replication. (Arrows indicate enhancement of responses, whereas blocked lines indicate inhibition).

Figure 2

Distinct roles for CD4⁺ T cell subpopulations in chronic Friend Retrovirus infection. During chronic infection, effector CD8⁺ T cell responses are suppressed by regulatory T cells but a subpopulation of effector CD4⁺ T cells prevents virus reactivation. (Blocked lines indicate inhibition of immune responses or virus replication; the dotted line indicates that this response is suppressed during chronic infection).