Expanding roles for CD4⁺ T cells in immunity to viruses

Abstract

Viral pathogens often induce strong effector CD4(+) T cell responses that are best known for their ability to help B cell and CD8(+) T cell responses. However, recent studies have uncovered additional roles for CD4(+) T cells, some of which are independent of other lymphocytes, and have described previously unappreciated functions for memory CD4(+) T cells in immunity to viruses. Here, we review the full range of antiviral functions of CD4(+) T cells, discussing the activities of these cells in helping other lymphocytes and in inducing innate immune responses, as well as their direct antiviral roles. We suggest that all of these functions of CD4(+) T cells are integrated to provide highly effective immune protection against viral pathogens.

Figure 1. Generation of antiviral effector CD4⁺ T cells.

The crucial initial steps in generating primary antiviral T cell responses are the uptake of viral antigens by antigen-presenting cells (APCs) in infected tissue, the activation of APCs by pattern-recognition receptor (PRR) ligation, and the migration of these cells to draining lymph nodes. The nature of the viral infection, as well as PRR ligation, can influence the activation status of antigen-bearing APCs and the T helper (T_H) cell-polarizing environment. The recognition of antigens on activated APCs by naive T cells during viral infection predominately results in the generation of T_H1 cells owing to the presence of type I interferons (IFNs) and interleukin-12 (IL-12). However, T_H17, T_H2 and regulatory T (T_Reg) cell populations are also generated to some degree in certain viral infections. TCR, T cell receptor; TGFβ, transforming growth factor-β; TNF, tumour necrosis factor.

Figure 2. Helper functions of CD4⁺ T cells.

a | The canonical function of CD4⁺ T cells is the provision of help for B cells in germinal centre formation, isotype switching and affinity maturation of antibody responses. Follicular helper T (T_FH) cells are a specialized subset of CD4⁺ T cells that provide help to B cells through both cell–cell interactions (most notably CD40L– CD40 interactions) and the release of cytokines. The generation of neutralizing antibodies is a crucial component of protection against many viral pathogens and the goal of most vaccine strategies. b | The best-characterized pathway of CD4⁺ T cell-mediated help in the generation of CD8⁺ T cell effectors involves the provision of interleukin-2 (IL-2) and the activation, known as 'licensing', of antigen-presenting cells (APCs) via CD40L–CD40 interactions. It is often unclear whether CD4⁺ T cell-mediated help has a role in the initial generation of antiviral CD8⁺ T cell effector responses, presumably because viruses can trigger pattern-recognition receptors and independently activate APCs. However, a clear role for CD4⁺ T cell-mediated help in the generation of functional memory CD8⁺ T cells has been demonstrated during viral infection. Downregulation of TNF-related apoptosis-inducing ligand (TRAIL) expression on CD8⁺ T cells is a prominent feature of CD8⁺ T cells that have been helped and at least in part facilitates their robust recall response during secondary infection. BCR, B cell receptor; ICOS, inducible T cell co-stimulator; ICOSL, ICOS ligand; TCR, T cell receptor; T_H, T helper.

Figure 3. Antiviral functions of CD4⁺ T cells that are independent of their lymphocyte helper functions.

a | After migrating to sites of infection, effector CD4⁺ T cells that recognize antigens on antigen-presenting cells (APCs) produce an array of effector cytokines that contribute to the character of the inflammatory responses in the tissue. Some products of highly activated effector CD4⁺ T cells, such as interleukin-10 (IL-10), dampen inflammation and regulate immunopathology, whereas others, such as interferon-γ (IFNγ), are pro-inflammatory and activate macrophages, which in turn drive further inflammation. The production of IL-10 by effector CD4⁺ T cells can have a profound impact on the outcome of a viral infection. b | IFNγ, tumour necrosis factor (TNF) and other cytokines produced by CD4⁺ T cells help to coordinate an antiviral state in infected tissues. c | Cytotoxic CD4⁺ T cells can directly lyse infected cells through diverse mechanisms, including FAS-dependent and perforin-dependent killing. FASL, FAS ligand; NK, natural killer; TCR, T cell receptor; TRAIL, TNF-related apoptosis-inducing ligand; TRAILR, TRAIL receptor.

Figure 4. Activation of APCs through PRRs and through the recognition of antigens by memory CD4⁺ T cells.

a | Several classes of pattern-recognition receptors (PRRs), such as Toll-like receptors (TLRs), sense the presence of viral pathogens, and the triggering of these receptors leads to the activation of antigen-presenting cells (APCs), including dendritic cells (DCs). Activated APCs upregulate their expression of MHC molecules and co-stimulatory molecules, which are important for the priming of naive virus-specific T cells. Triggering of PRRs at the site of infection induces local inflammation, which involves the activation of several populations of innate immune cells that can control viral titres and establish chemokine gradients to attract further antiviral effector cells. The efficiency of PRR triggering can determine whether viral replication or protective immunity gains the upper hand. b | Virus-specific memory CD4⁺ T cells can directly activate DCs through the recognition of antigens presented by MHC class II molecules, even in the absence of co-stimulation delivered via PRR-mediated signalling. The crucial signals delivered by memory CD4⁺ T cells to DCs in this process are unclear and could involve both cell-surface interactions and cytokine signals. The outcome of DC activation and the initiation of inflammatory responses are similar whether triggered through PRRs or memory CD4⁺ T cells but, in situations of infection with a rapidly replicating virus (such as influenza virus), memory CD4⁺ T cell-mediated enhancement of innate immunity is substantially quicker and more effective than that provided by PRR triggering. TCR, T cell receptor.