During chronic infections and cancer, T cells progressively drop function and become worn out. peptides is usually abrogated when CD4 T cells are depleted, showing that CD4 T cells sustain anti-HIV CD8 T-cell responses . In many situations CD8 T cells rely on CD4 T-cell help in the form of DC licensing (Physique PLX8394 1A) in order to undergo efficient priming and appropriate differentiation into memory cells. Shortly after antigen recognition, CD4 T cells express CD40L and activate DCs presenting cognate antigen through CD40 cross-linking [21C23]. Additionally, direct CD40 ligation on CD8 T cells by cognate CD40L+ CD4 T cells may also play a role on CD8 T-cell activation (Figure 1A) . Still, it is well established that CD4-licensed DCs become activated and better APCs due to increased expression of costimulatory molecules and enhanced ability to secrete cytokines such as IL-1, IL-6, TNF- and IL-15 . Although some reports argue that viral infections may provide enough inflammatory signals to directly induce optimal DC activation, in a chronic infection setting, when acute inflammatory signals have waned, CD4 help may be critical to activate DCs presenting viral antigens to promote rescue of exhausted CD8 T cells. Open in a separate window Figure 1 CD4 T cells can reinvigorate immune responses by activating different arms of the immune systemDuring 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 PLX8394 surface of APCs (i), and it PLX8394 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 Rabbit polyclonal to GRB14 cells can orchestrate and restore endogenous antiviral responses to promote viral control. (C) Pleiotropic antiviral effects. Increased production of IFN- and TNF- (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- and TNF- 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 PLX8394 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: PeptideCMHC complex; BCR: B-cell receptor; TCR: T-cell receptor. CD4 T cells can also modulate CD8 T-cell recruitment and migration. Activated CD4 T cells and CD4-licensed DCs PLX8394 produce chemokines, such as CCL3 (MIP-1) and CCL4 (MIP-1) that attract CD8 T cells to sites where APCs have cognate antigen . In addition, IFN- production by activated CD4 T cells can trigger the surrounding tissue to secrete CXCL9 and CXCL10, which are required to attract effector CD8 T cells to some infection sites, as demonstrated for vaginal HSV-2 infection in mice . CD4 helper T cells also secrete cytokines that can directly impact exhausted CD8 T cells (Figure 1A). IL-2 administration to LCMV chronically infected mice, induces proliferation of LCMV-specific CD8 T cells and results in decreased viral burden . IL-2 production by CD4 T cells has also been shown to play an important role for antiviral CD8 T-cell function in HIV and HCV infection [14,28]. In addition, IL-21 production by CD4 T cells sustains LCMV-specific CD8 T-cell responses during chronic infection [29C31]. Likewise, experiments have shown that IL-21 can enhance functionality of exhausted.