Induction and function of virus-specific CD4+ T cell responses

Abstract

CD4+ T cells - often referred to as T-helper cells - play a central role in immune defense and pathogenesis. Virus infections and vaccines stimulate and expand populations of antigen-specific CD4+ T cells in mice and in man. These virus-specific CD4+ T cells are extremely important in antiviral protection: deficiencies in CD4+ T cells are associated with virus reactivation, generalized susceptibility to opportunistic infections, and poor vaccine efficacy. As described below, CD4+ T cells influence effector and memory CD8+ T cell responses, humoral immunity, and the antimicrobial activity of macrophages and are involved in recruiting cells to sites of infection. This review summarizes a few key points about the dynamics of the CD4+ T cell response to virus infection, the positive role of pro-inflammatory cytokines in the differentiation of virus-specific CD4+ T cells, and new areas of investigation to improve vaccines against virus infection.

Figure 1. The central role of virus-specific CD4 T cells in immune defense

Antiviral CD4+ T cells affect multiple wings of the immune system to protect against infection. CD4+ T cells interact directly with antigen presenting cells to enhance their ability to present viral antigen to T cells. They engage B cells and direct their differentiation into memory B cells and plasma cells and affect the kind of antibody that is made. CD4+ T cells can directly suppress virus infection in MHCII+ target cells. CD4+ T cells are essential for the induction of antiviral CD8+ T cell responses to many infections and enhance the protective recall response of memory CD8+ T cells.

Figure 2. The T cell response following acute LCMV infection in mice

The T cell response following acute LCMV infection provides a well-defined model to study how CD4+ T cells, CD8+ T cells, and B cells responses develop. The graph shows the dramatic increase in number of virus-specific T cells after infection and the establishment of elevated numbers of memory T cells. The innate immune response begins immediately after infection and affects the subsequent T cell response. Responding T cells produce interferon-gamma and express other molecules that impact their expansion in number and differentiation into memory cells. The essential patterns are shown for a robust acute infection, but other infections show smaller or delayed responses that are related to differences in the magnitude or duration of infection and variations in the inflammatory environment.

Figure 3. Selection of the fittest: virus-specific CD4+ T cells compete for antigen and cytokines, selecting and enriching for high quality memory cells

Antiviral CD4+ T cells respond to antigen and inflammation by undergoing cell-division, which can be incredibly rapid. As they accumulate in number, effector T cells begin to compete for access to antigen, which constrains cell-division for cells that weakly interact with antigen. In addition, the most vigorously responding T cells produce IFNγ and receive direct IFNγ signals; the best responders receive the greatest amount of IFNγ signaling and continue to accumulate. IFNγ signals also enhance memory cell formation. It is unclear if direct IFNγ signals activate a program of memory cell differentiation or increase the number of memory cell precursors that have the potential to survive.