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⇱ Expanding roles for CD4+ T cells in immunity to viruses | Nature Reviews Immunology

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Key Points

  • CD4+ T cells are orchestrators, regulators and direct effectors of antiviral immunity.

  • Neutralizing antibodies provide protection against many viral pathogens, and CD4+ T cells can help B cells to generate stronger and longer-lived antibody responses.

  • CD4+ T cells help antiviral CD8+ T cells in two main ways: they maximize CD8+ T cell population expansion during a primary immune response and also facilitate the generation of virus-specific memory CD8+ T cell populations.

  • In addition to their helper functions, CD4+ T cells contribute directly to viral clearance. They secrete cytokines with antiviral activities and, in some circumstances, can eliminate infected cells through cytotoxic killing.

  • Memory CD4+ T cells provide superior protection during re-infection with a virus. Compared with new effector CD4+ T cells, memory CD4+ T cells have enhanced helper and effector functions and can rapidly trigger innate immune defence mechanisms early in the infection.

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.

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Figure 1: Generation of antiviral effector CD4+ T cells.
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Figure 2: Helper functions of CD4+ T cells.
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Figure 3: Antiviral functions of CD4+ T cells that are independent of their lymphocyte helper functions.
The alternative text for this image may have been generated using AI.
Figure 4: Activation of APCs through PRRs and through the recognition of antigens by memory CD4+ T cells.
The alternative text for this image may have been generated using AI.

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Acknowledgements

We apologize to the many authors whose papers could not be cited owing to space limitations. We are grateful to R. W. Dutton for critical reading of the manuscript and insightful discussions. The authors are supported by grants from the US National Institutes of Health.

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  1. Department of Pathology, University of Massachusetts Medical School, 55 Lake Avenue N, Worcester, 01655, Massachusetts, USA

    Susan L. Swain, K. Kai McKinstry & Tara M. Strutt

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  1. Susan L. Swain
  2. K. Kai McKinstry
  3. Tara M. Strutt

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Correspondence to Susan L. Swain.

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Glossary

Pattern-recognition receptors

(PRRs). Host receptors that can detect pathogen-associated molecular patterns and initiate signalling cascades, leading to an innate immune response. Examples include Toll-like receptors (TLRs) and NOD-like receptors (NLRs). PRRs can be membrane-bound receptors (as in the case of TLRs) or soluble cytoplasmic receptors (as in the case of NLRs, retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5)).

T-bet

A member of the T-box family of transcription factors. T-bet is a master switch in the development of T helper 1 (TH1) cell responses through its ability to regulate the expression of the interleukin-12 receptor, inhibit signals that promote TH2 cell development and promote the production of interferon-Ξ³.

Class switching

The process by which proliferating B cells rearrange their DNA to switch from expressing the heavy-chain constant region of IgM (or another class of immunoglobulin) to expressing that of a different immunoglobulin class, thereby producing antibodies with different effector functions. The decision of which isotype to generate is strongly influenced by the specific cytokine milieu and by other cells, such as T helper cells.

Germinal centre

A highly specialized and dynamic microenvironment that gives rise to secondary B cell follicles during an immune response. Germinal centres are the main site of B cell maturation, which leads to the generation of memory B cells and plasma cells that produce high-affinity antibodies.

Polyinosinic–polycytidylic acid

(PolyI:C). A substance that is used as a mimic of viral double-stranded RNA.

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Swain, S., McKinstry, K. & Strutt, T. Expanding roles for CD4+ T cells in immunity to viruses. Nat Rev Immunol 12, 136–148 (2012). https://doi.org/10.1038/nri3152

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