Figure 1. CD4 T cells can reinvigorate immune responses by activating different arms of the immune system.

During chronic lymphocytic choriomeningitis virus (LCMV) infection, virus-specific CD8 T cells are exhausted and B cells are not engaged in effective antiviral responses. (A) CD8 help. Adoptive transfer of LCMV-specific CD4 T cells into chronically infected mice rescues CD8 T cells. CD4 T cells may provide help to cognate CD8 T cells by licensing APCs. Activated CD4 T cells express CD40L, which crosslinks CD40 on the surface of APCs (i), and it may also provide direct signals to CD8 T cells (ii). (i) CD40 crosslinking on APCs induces an increase in MHC class I expression and costimulatory B7 molecules, which enhance antigen presentation and CD8 T-cell activation. (ii) Activated CD4 T cells secrete cytokines that directly enhance function of exhausted CD8 T cells (e.g., IL-21 and IL-2). (B) B-cell help. CD4 T cells provide help to cognate B cells in the form of CD40 ligation and IL-21. B cells that receive T-cell help in the germinal center reaction are selected to become memory B cells or plasma cells. Hence, adoptive transfer of LCMV-specific CD4 T cells can orchestrate and restore endogenous antiviral responses to promote viral control. (C) Pleiotropic antiviral effects. Increased production of IFN-γ and TNF-α (derived from both transferred CD4 T cells and rescued endogenous CD8 T cells) can recruit and activate effector cells from the innate immune system (e.g., macrophages, monocytes, eosinophils, neutrophils and NK cells). In addition, IFN-γ and TNF-α can have direct effects on infected cells, by inhibiting viral replication and also promoting cell death. Importantly, during chronic infections, exhausted CD8 T cells express the inhibitory receptor PD-1, and PD-1 ligands are ubiquitously expressed during persistent inflammation. Therefore, CD8 T-cell rescue is limited by the PD-1 pathway. In addition, CD4 T cells also express PD-1 upon activation and are not optimally functional in chronically infected hosts. Thus, blockade of the PD-1 pathway in combination with adoptive transfer of CD4 T cells results in enhanced function of transferred CD4 T cells and improved rescue of CD8 T cells that ultimately leads to superior viral control. Similar scenarios could also be envisaged for the treatment of other chronic infections, as well as cancer.

For more information, please see [1,13,50].

pMHC: Peptide–MHC complex; BCR: B-cell receptor; TCR: T-cell receptor.