Trends in Molecular Medicine
Feature ReviewCD4+ T Cell Differentiation in Chronic Viral Infections: The Tfh Perspective
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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Cited by (41)
Immune checkpoint expression on HIV-specific CD4+ T cells and response to their blockade are dependent on lineage and function
2022, eBioMedicineCitation Excerpt :The other combinations followed the expected trends (Figure S3d): IL22 mRNA-expressing cells were greater in EC, whereas the CP had higher frequencies of all TFH-related cytokines combinations. While the sizes of the cohorts were small for the TH1-associated combinations, IFNG single-positive cells were the greatest population of all antiviral-related constellations among CP, consistent with the reported loss of polyfunctionality in HIV-specific TH1.39 Cytokine mRNA production following strong stimulation with the unspecific superantigen SEB showed no differences between the cohort (Figure S3e), suggesting that aforementioned differences are characteristics of HIV-specific CD4+ T cells.
DOCK8-expressing T follicular helper cells newly generated beyond self-organized criticality cause systemic lupus erythematosus
2022, iScienceCitation Excerpt :Previous studies have shown that, upon encounter with peripherally expressed antigens such as mouse mammary tumor virus (Mtv-8) or influenza hemagglutinin (HA), the CD4 T cells reactive against them are deleted or anergized (St. Rose et al., 2009; Higdon et al., 2014). However, further repeated stimulation causes a few cells to be resuscitated from anergy, proliferate, and pass through TCR re-revision at the periphery, acquiring a T follicular helper-like phenotype (St. Rose et al., 2009; Crawford et al., 2014; Higdon et al., 2014; Vella et al., 2017). Because these cells no longer react against the same antigens and reside in a restricted space, splenic GC, immune response will cease (Higdon et al., 2014).
T cell immunity to SARS-CoV-2
2021, Seminars in ImmunologyCitation Excerpt :T cells are broadly divided up into two subsets: The first one, T helper cells (CD4+ T cells), orchestrate different arms of the immune system and are critical in the defense against both extracellular and intracellular pathogens. Following viral infections, naïve CD4+ T cells differentiate mainly into two subsets, known as T helper 1 (Th1) and T follicular helper (Tfh) cells (reviewed in [4]). Th1 promote cell-mediated immune responses by activating other immune cells to control viral spread, while Tfh provide B cell help by mediating somatic hypermutations and affinity maturation of germinal center reactions, leading to the generation of high-affinity antibodies capable of neutralizing viruses.
Dynamic adoption of anergy by antigen-exhausted CD4<sup>+</sup> T cells
2021, Cell ReportsCitation Excerpt :They also recall results on LCMV- and liver/cancer-exhausted CD8+ T cells whose phenotype remained flexible for around 2 weeks of chronic stimulation (Angelosanto et al., 2012; Philip et al., 2017). It has been discussed whether CD4+ Th1 cells are merely dysfunctional in chronic infections (Brooks et al., 2006) or differentiate into T follicular helper (Tfh) cells (Crawford et al., 2014; Fahey et al., 2011) or another cell type able to deliver help to CD8+ T cells via IL-21 (Vella et al., 2017). We noticed that several mRNAs associated with T-B cell interaction and Maf, Tox, CXCR5, and ICOS proteins were affected by antigen persistence (Kroenke et al., 2012; Xu et al., 2019; Figures 6B and 7A).
Persistent expansion and Th1-like skewing of HIV-specific circulating T follicular helper cells during antiretroviral therapy
2020, EBioMedicineCitation Excerpt :In contrast, other studies observed a Tfh expansion and Th1-phenotype in other chronic infections that share some features with HIV, such as LCMV clone 13 in mice [5], SIV in non-human primates [50], HCV [6], and malaria [51], in humans. The underlying mechanisms are poorly understood, but several studies suggested that increased duration of Ag exposure, high levels of Ag and inflammatory cytokines, common for these infections, favor this polarization (reviewed in [52]). Two non-mutually exclusive mechanisms may be responsible for maintaining the characteristics of virus-specific CD4+ T cell responses during viral suppression on ART.