Trends in Molecular Medicine
Volume 23, Issue 12, December 2017, Pages 1072-1087
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Feature Review
CD4+ T Cell Differentiation in Chronic Viral Infections: The Tfh Perspective

https://doi.org/10.1016/j.molmed.2017.10.001Get rights and content

Trends

Chronic viral infections can impair CD4+ T cell responses, with a loss of Th1 function.

CD4+ T cells are skewed towards a Tfh lineage during chronic viral infections in mice and in humans and away from a potentially more antiviral Th1 state.

A Tfh-like program can also occur in some CD8+ T cells; perhaps giving these cells access to the B cell follicle where they might interact with viral reservoirs.

Increased Tfh cells may assist CD8+ T cells and prevent immune-mediated damage when a viral infection cannot be cleared.

Tfh cells provide help to B cells for antibody class switching and affinity maturation, but despite a Tfh bias in chronic viral infections, effective humoral immunity is often impaired.

CD4+ T cells play a critical role in the response to chronic viral infections during the acute phase and in the partial containment of infections once chronic infection is established. As infection persists, the virus-specific CD4+ T cell response begins to shift in phenotype. The predominant change described in both mouse and human studies of chronic viral infection is a decrease in detectable T helper type (Th)1 responses. Some Th1 loss is due to decreased proliferative potential and decreased cytokine production in the setting of chronic antigen exposure. However, recent data suggest that Th1 dysfunction is accompanied by a shift in the differentiation pathway of virus-specific CD4+ T cells, with enrichment for cells with a T follicular helper cell (Tfh) phenotype. A Tfh-like program during chronic infection has now been identified in virus-specific CD8+ T cells as well. In this review, we discuss what is known about CD4+ T cell differentiation in chronic viral infections, with a focus on the emergence of the Tfh program and the implications of this shift with respect to Tfh function and the host–pathogen interaction.

Section snippets

Viral Infections and the T Cell Response

Chronic infections are a ubiquitous part of human history and can lead to dysfunction and neoplastic transformation (see Glossary) of infected cells and affected organs [1]. Chronic infection can additionally lead to dysfunction of responding immune cells. However, many of these infections contribute to the shape of the normal immune system. For example, laboratory mice have less-mature immune systems than mice experimentally infected with multiple pathogens or cohoused with so-called dirty or

CD4+ T Cell Responses in LCMV Infection

The study of LCMV in mice has provided many cellular and mechanistic insights into immune responses to chronic infections. LCMV exists in the form of acutely resolving strains such as Armstrong (Arm) and chronic strains, such as clone 13 and WE. These viruses differ in a few amino acids that lead to dramatic differences in the ability of the immune system to clear infection [54]. Following infection of immunocompetent mice with acute strains of LCMV, virus is cleared by days 8–10 postinfection.

CD4+ T Cells in Human and Nonhuman Primate Chronic Viral Infections

A major goal of studying chronic infections in mice is to understand, prevent, and treat human disease. Our ability to translate findings from mice to humans has faced several challenges. First, understanding how the immune response changes as a pathogen transitions from an acute to a chronic infection requires the identification of patients in acute stages of infection. Cohorts developed to track high-risk patients have provided invaluable samples and datasets in recent years 80, 81. However,

Concluding Remarks

Chronic infections are a normal part of human immune development that can be contained by, but also alter, CD4+ T cell responses 1, 2, 3. Collectively, LCMV, HCV, SIV, and HIV-1 infections indicate a direct relationship between chronic viral infection and Tfh cell biology. The pathways that drive Tfh differentiation are incompletely understood and may include features of both chronic antigen stimulation and of a shifting inflammatory environment. Moreover, while Tfh cells in chronic infection

Acknowledgments

L.A.V. was supported by NIH grant KL2TR001879. R.S.H. was supported by the NIH grants AI114852 and AG047773. Work in the Wherry Laboratory is supported by the Penn Center for Aids Research (P30 AI045008), the National Institutes of Health (NIH) grants AI112521, AI115977, AI117950, AI105343, and AI082630, as well as the U.S. Broad Agency Announcements grant NIHAI2010085. E.J.W. is also supported by the Parker Institute for Cancer Immunotherapy.

Glossary

Activation induced markers
proteins upregulated on the cell surface following activating signals through the TCR.
Affinity maturation
progressive selection of higher affinity B cell-produced antibodies.
Anti-PD-1 immunotherapy
type of checkpoint blockade immunotherapy that binds to PD-1 on the T cell surface and blocks PD-1 inhibitory signaling.
Antiretroviral therapy
combination therapy directed against different stages of the HIV-1 life cycle, usually consisting of two or three medications.
B cell

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