scholarly journals Opposing effects of T cell receptor signal strength on CD4 T cells responding to acute versus chronic viral infection

2020 ◽  
Author(s):  
Marco Künzli ◽  
Peter Reuther ◽  
Daniel D. Pinschewer ◽  
Carolyn G. King
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
Cell Fate ◽  
Cd4 T Cells ◽  
Chronic Infection ◽  
Signal Strength ◽  
Cd4 T Cell ◽  
Chronic Viral Infection ◽  
Tfh Cells

AbstractA hallmark of the adaptive immune response is the ability of CD4 T cells to differentiate into a variety of pathogen appropriate and specialized effector subsets. A long-standing question in CD4 T cell biology is whether the strength of TCR signals can instruct one Th cell fate over another. The contribution of TCR signal strength to the development of Th1 and T follicular helper (Tfh) cells has been particularly difficult to resolve, with conflicting results reported in a variety of models. Although cumulative TCR signal strength can be modulated by the infection specific environment, whether or not TCR signal strength plays a dominant role in Th1 versus Tfh cell fate decisions across distinct infectious contexts is not known. Here we characterized the differentiation of CD4 TCR transgenic T cells responding to a panel of recombinant wild type or altered peptide ligand lymphocytic choriomeningitis viruses (LCMV) derived from acute and chronic parental strains. We found that while TCR signal strength positively regulates T cell expansion in both infection settings, it exerts opposite and hierarchical effects on the balance of Th1 and Tfh cells generated in response to acute versus persistent infection. The observation that weakly activated T cells, which comprise up to fifty percent of an endogenous CD4 T cell response, support the development of Th1 effectors highlights the possibility that they may resist functional inactivation during chronic infection. We anticipate that the panel of variant ligands and recombinant viruses described herein will be a valuable tool for immunologists investigating a wide range of CD4 T cell responses.Graphical abstractHighlightsIdentification of a wide panel of altered peptide ligands for the LCMV-derived GP61 peptideGeneration of LCMV variant strains to examine the impact of TCR signal strength on CD4 T cells responding during acute and chronic viral infectionThe relationship between TCR signal strength and Th1 differentiation shifts according to the infection context: TCR signal strength correlates positively with Th1 generation during acute infection but negatively during chronic infection.

scholarly journals T Cell–Intrinsic CX3CR1 Marks the Most Differentiated Effector CD4+ T Cells, but Is Largely Dispensable for CD4+ T Cell Responses during Chronic Viral Infection

2020 ◽  
Vol 4 (11) ◽  
pp. 701-712
Author(s):  
Nathália V. Batista ◽  
Yu-Han Chang ◽  
Kuan-Lun Chu ◽  
Kuan Chung Wang ◽  
Mélanie Girard ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
Cd4 T Cells ◽  
T Cell Responses ◽  
Cd4 T Cell ◽  
Chronic Viral Infection ◽  
Cell Responses

scholarly journals IL-21 from high-affinity CD4 T cells drives differentiation of brain-resident CD8 T cells during persistent viral infection

2020 ◽  
Vol 5 (51) ◽  
pp. eabb5590 ◽  
Author(s):  
Heather M. Ren ◽  
Elizabeth M. Kolawole ◽  
Mingqiang Ren ◽  
Ge Jin ◽  
Colleen S. Netherby-Winslow ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Central Nervous System Infection ◽  
Cell Receptor ◽  
Cd4 T Cell ◽  
Persistent Viral Infection ◽  
High Affinity

Development of tissue-resident memory (TRM) CD8 T cells depends on CD4 T cells. In polyomavirus central nervous system infection, brain CXCR5hi PD-1hi CD4 T cells produce interleukin-21 (IL-21), and CD8 T cells lacking IL-21 receptors (IL21R−/−) fail to become bTRM. IL-21+ CD4 T cells exhibit elevated T cell receptor (TCR) affinity and higher TCR density. IL21R−/− brain CD8 T cells do not express CD103, depend on vascular CD8 T cells for maintenance, are antigen recall defective, and lack TRM core signature genes. CD4 T cell–deficient and IL21R−/− brain CD8 T cells show similar deficiencies in expression of genes for oxidative metabolism, and intrathecal delivery of IL-21 to CD4 T cell–depleted mice restores expression of electron transport genes in CD8 T cells to wild-type levels. Thus, high-affinity CXCR5hi PD-1hi CD4 T cells in the brain produce IL-21, which drives CD8 bTRM differentiation in response to a persistent viral infection.

A Variety of T-Cell Subsets Contribute to CD4+ T-Cell Infiltration in Diffuse Large B-Cell Lymphoma and Both Total CD4+ and CD4+FoxP3+ T-Cell Numbers Predict Clinical Outcome,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3684-3684
Author(s):  
Matthew J Ahearne ◽  
Kaljit S Bhuller ◽  
Roger Hew ◽  
Giovanna Roncador ◽  
Martin J.S. Dyer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Clinical Outcome ◽  
Cd4 T Cells ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
Cell Infiltration ◽  
Good Clinical Outcome ◽  
Logrank Test ◽  
Tfh Cells

Abstract Abstract 3684 CD4+ T-cells can be distinguished into subsets on the basis of surface marker expression and growth factor production. Follicular helper T-cells (Tfh cells) are characterized by the co-expression of surface markers (CD4, ICOS, PD1 and CXCR5) and nuclear BCL6. Normal germinal centre formation requires Tfh cells but is repressed by another CD4+ T-cell subset, Tregs, (demonstrating CD4 and CD25 expression with nuclear FoxP3). The numbers and architecture of infiltrating T-cells predict clinical outcome in follicular lymphoma but although T-cells are a component of diffuse large B cell lymphoma (DLBCL), the relative numbers of CD4+ T-cells and their Tfh and Treg subsets or their association with clinical outcome is not known. We used immunohistochemistry to investigate infiltration by total CD4+, Treg and Tfh cells in cases (n=23) from one centre. The male:female was 1.3:1.0, the age range was 30 to 78 years (median 65 years) and the anticipated association between overall survival and LDH (logrank test, P=0.02) was observed. Patients were treated with R-CHOP with a 21-day cycle. Histological sections were stained with anti-CD4, anti-PD1 and anti-FoxP3 antibodies. For each antibody the area of staining was measured using ImageJ software from 10 high power fields from the same area of each histological section. Tfh cells were identified by strong surface expression of PD1 and Tregs by nuclear expression of FoxP3. CD4+ T-cell infiltration varied by ∼50-fold, and could be diffuse or focal. In 13 cases (57%) the majority of CD4+ T-cells were neither FoxP3+ nor PD1+. Total CD4+ T-cell numbers were positively correlated with FoxP3 (P=0.04) (Figure 1) and with PD1 (P=0.009) (Figure 2) expressing cells suggesting that these subsets were expanded as part of a reaction to the lymphoma capable of stimulating several CD4+ T-cell subsets. High CD4+ (Figure 3) and PD1+ staining predicted good clinical outcome (logrank test, P=0.08) with median survival not being reached at 5 years, but the amount of FoxP3+ staining appeared to be a superior prognostic marker (logrank test, P=0.0069) (Figure 4). There was no association between the cell of origin classification of DLBCL (GCB or ABC) as defined immunohistochemically, and CD4, FoxP3 or PD1 expression. In summary, we have shown that numbers of infiltrating CD4+ T-cells vary between cases of DLBCL and comprises several T-cell subsets including Treg and Tfh cells. No consensus has been reached on the clinical significance of FoxP3+ cell infiltration in DLBCL. Whilst some workers have shown FoxP3 to be associated with a good clinical outcome (Tzankov A., et al. 2008; Lee N., et al. 2008), others have not found a relationship to prognosis (Hasselblom S. et al., 2007). Our data shows that the FoxP3+ Treg cell subset is associated with good clinical outcome but surprisingly we found that both increased total CD4+ T-cells and PD1+ Tfh cells also carry a good prognosis. Disclosures: Wagner: Roche: Honoraria.

scholarly journals CD4+T-cell inhibitory ligands: a tool for characterizing dysfunctional CD4+T cells during chronic infection

Immunology ◽  
2013 ◽  
Vol 140 (1) ◽  
pp. 61-69 ◽  
Author(s):  
Courtney Dow ◽  
Ryan Henderson ◽  
Alessandro Sette ◽  
Bianca R. Mothé
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Chronic Infection ◽  
Cd4 T Cell

scholarly journals Antigen-specific CD4 T-cell help rescues exhausted CD8 T cells during chronic viral infection

2011 ◽  
Vol 108 (52) ◽  
pp. 21182-21187 ◽  
Author(s):  
R. D. Aubert ◽  
A. O. Kamphorst ◽  
S. Sarkar ◽  
V. Vezys ◽  
S.-J. Ha ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
Cd8 T Cells ◽  
Cd4 T Cell ◽  
Chronic Viral Infection ◽  
Cd4 T Cell Help ◽  
T Cell Help

scholarly journals Direct Infection of Dendritic Cells during Chronic Viral Infection Suppresses Antiviral T Cell Proliferation and Induces IL-10 Expression in CD4 T Cells

PLoS ONE ◽  
2014 ◽  
Vol 9 (3) ◽  
pp. e90855 ◽  
Author(s):  
Carmen Baca Jones ◽  
Christophe Filippi ◽  
Sowbarnika Sachithanantham ◽  
Teresa Rodriguez-Calvo ◽  
Katrin Ehrhardt ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Viral Infection ◽  
Cd4 T Cells ◽  
T Cell Proliferation ◽  
Chronic Viral Infection

Mechanisms of anti-viral Cytotoxic CD4 T cell differentiation

2021 ◽  
Author(s):  
Cory J. Knudson ◽  
Maria Férez ◽  
Pedro Alves-Peixoto ◽  
Dan A. Erkes ◽  
Carolina R. Melo-Silva ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factors ◽  
T Cell ◽  
Viral Infection ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Transcriptional Analysis ◽  
Th1 Cells ◽  
T Helper ◽  
T Helper 1

Cytotoxic CD4 T lymphocytes (CD4-CTL) are important in anti-viral immunity. For example, we have previously shown that in mice, CD4-CTL are important to control ectromelia virus (ECTV) infection. How viral infections induce CD4-CTL responses remains incompletely understood. Here we demonstrate that not only ECTV but also vaccinia virus and Lymphocytic Choriomeningitis virus induce CD4-CTL, but that the response to ECTV is stronger. Using ECTV, we also demonstrate that in contrast to CD8-CTL, CD4-CTL differentiation requires constant virus replication and ceases once the virus is controlled. We also show that Major Histocompatibility Complex Class II molecules on CD11c + cells are required for CD4-CTL differentiation and for mousepox resistance. Transcriptional analysis indicated that anti-viral CD4-CTL and non-cytolytic T Helper 1 (Th1) CD4 T cells have similar transcriptional profiles, suggesting that CD4-CTL are terminally differentiated classical Th1 cells. Interestingly, CD4-CTL and classical Th1 cells expressed similar mRNA levels of the transcription factors ThPOK and GATA-3, necessary for CD4 T cell linage commitment; and Runx3, required for CD8 T cell development and effector function. However, at the protein level, CD4-CTL had higher levels of the three transcription factors suggesting that further post-transcriptional regulation is required for CD4-CTL differentiation. Finally, using CRISPR-Cas9 deletion of Runx3 in CD4 T cells, we demonstrate that the development of CD4-CTL but not of classical Th1 CD4 T cells requires Runx3 following ECTV infection. These results further our understanding of the mechanisms of CD4-CTL differentiation during viral infection and the role of post-transcriptionally regulated Runx3 in this process. IMPORTANCE While it is well established that cytotoxic CD4 T cells (CD4-CTL) directly contribute to viral clearance, it remains unclear how CD4-CTL are induced. We now show that CD4-CTL require sustained antigen presentation and are induced by CD11c-expressing antigen presenting cells. Moreover, we show that CD4-CTL are derived from the terminal differentiation of classical T helper 1 (Th1) subset of CD4 cells. Compared to Th1 cells, CD4-CTL upregulate protein levels of the transcription factors ThPOK, Runx3 and GATA-3 post-transcriptionally. Deletion of Runx3 in differentiated CD4 T cells prevents CD4-CTL but not of classical Th1 cells. These results advance our knowledge of how CD4-CTL are induced during viral infection.

scholarly journals Viral persistence redirects CD4 T cell differentiation toward T follicular helper cells

2011 ◽  
Vol 208 (5) ◽  
pp. 987-999 ◽  
Author(s):  
Laura M. Fahey ◽  
Elizabeth B. Wilson ◽  
Heidi Elsaesser ◽  
Chris D. Fistonich ◽  
Dorian B. McGavern ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
Cd4 T Cells ◽  
Viral Infections ◽  
Viral Persistence ◽  
Cd4 T Cell ◽  
T Follicular Helper Cells ◽  
Helper Cells ◽  
Follicular Helper

CD4 T cell responses are crucial to prevent and control viral infection; however, virus-specific CD4 T cell activity is considered to be rapidly lost during many persistent viral infections. This is largely caused by the fact that during viral persistence CD4 T cells do not produce the classical Th1 cytokines associated with control of acute viral infections. Considering that CD4 T cell help is critical for both CD8 T cell and B cell functions, it is unclear how CD4 T cells can lose responsiveness but continue to sustain long-term control of persistent viral replication. We now demonstrate that CD4 T cell function is not extinguished as a result of viral persistence. Instead, viral persistence and prolonged T cell receptor stimulation progressively redirects CD4 T cell development away from the Th1 response induced during an acute infection toward T follicular helper cells. Importantly, this sustained CD4 T cell functionality is critical to maintain immunity and ultimately aid in the control of persistent viral infection.

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