Vaccine Induced Distinct Circulating Memory CD4+ T-cells with T-follicular Helper Cell Commitment in Humans

AbstractMesenteric lymph nodes (MLNs), that drain the large and small intestine, are critical sites for the induction of oral tolerance. Although depletion of CD4 T cells in the intestinal lamina propria is a hallmark of HIV infection, CD4 T cell dynamics in MLNs is less known due to the lack of accessibility to these LNs. We demonstrate the early loss of memory CD4 T cells, including T follicular helper cells (Tfh) and a remodeling of MLN architecture in SIV-infected rhesus macaques (RMs). Along with the loss of Tfh cells, we observe the loss of memory B cells and of germinal center B cells. Tfh cells display a Th1 profile with increased levels of the transcription factors that negatively impact on Tfh differentiation and of Stat5 phosphorylation. MLNs of SIV-infected RMs display lower mRNA transcripts encoding for IL-12, IL-23, and IL-35, whereas those coding for IL-27 are not impaired in MLNs. In vitro, IL-27 negatively impacts on Tfh cells and recapitulates the profile observed in SIV-infected RMs. Therefore, early defects of memory CD4 T cells, as well of Tfh cells in MLNs, which play a central role in regulating the mucosal immune response, may have major implications for Aids.

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γδ T cells control humoral immune response by inducing T follicular helper cell differentiation

Nature Communications ◽

10.1038/s41467-018-05487-9 ◽

2018 ◽

Vol 9 (1) ◽

Cited By ~ 12

Author(s):

Rafael M. Rezende ◽

Amanda J. Lanser ◽

Stephen Rubino ◽

Chantal Kuhn ◽

Nathaniel Skillin ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Cell Differentiation ◽

Humoral Immune Response ◽

Γδ T Cells ◽

Helper Cell ◽

Humoral Immune ◽

Follicular Helper ◽

T Follicular Helper Cell

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Tracking the kinetics and phenotype of spike epitope-specific CD4 T cell immunity in the context of SARS-CoV-2 infection and vaccination

10.21203/rs.3.rs-957030/v1 ◽

2021 ◽

Author(s):

Jennifer Juno ◽

Kathleen Wragg ◽

Wen Shi Lee ◽

Thakshila Amarasena ◽

Arnold Reynaldi ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Critical Role ◽

Cd4 T Cell ◽

Public And Private ◽

Follicular Helper ◽

Cell Immunity ◽

Cell Clones ◽

Memory Cd4 T Cells

Abstract CD4+ T cells play a critical role in the immune response to viral infection. SARS-CoV-2 infection and vaccination elicit strong CD4+ T cell responses to the viral spike protein, including circulating T follicular helper (cTFH) cells that correlate with the development of neutralising antibodies. Here we use a novel HLA-DRB1*15:01/S751 tetramer to precisely track spike-specific CD4+ T cells following recovery from mild/moderate COVID-19, or after vaccination with spike-encoding vaccines. SARS-CoV-2 infection induces robust S751-specific responses with both CXCR5- and cTFH phenotypes that are maintained for at least 12 months in a stable, CXCR3-biased, central memory pool. Vaccination of immunologically naïve subjects similarly drives expansion of S751-specific T cells with a highly restricted TCR repertoire comprised of both public and private clonotypes. Vaccination of convalescent individuals drives recall of CD4+ T cell clones established during infection, which are shared between the CXCR5- and cTFH compartments. This recall response is evident 5 days after antigen exposure and includes a population of spike-specific cTFH that persist in the periphery after losing expression of PD-1. Overall this study demonstrates the generation of a stable pool of cTFH and memory CD4+ T cells that can be recalled upon spike antigen re-exposure, which may play an important role in long-term protection against SARS-CoV-2 infection.

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Fingolimod retains cytolytic T cells and limits T follicular helper cell infection in lymphoid sites of SIV persistence

PLoS Pathogens ◽

10.1371/journal.ppat.1008081 ◽

2019 ◽

Vol 15 (10) ◽

pp. e1008081 ◽

Cited By ~ 8

Author(s):

Maria Pino ◽

Sara Paganini ◽

Claire Deleage ◽

Kartika Padhan ◽

Justin L. Harper ◽

...

Keyword(s):

T Cells ◽

Helper Cell ◽

Cell Infection ◽

Follicular Helper ◽

T Follicular Helper Cell

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Faculty Opinions recommendation of Distinct memory CD4+ T cells with commitment to T follicular helper- and T helper 1-cell lineages are generated after acute viral infection.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718000228.793481877 ◽

2013 ◽

Author(s):

Xian C Li ◽

Picheng Zhao

Keyword(s):

T Cells ◽

Viral Infection ◽

Cd4 T Cells ◽

T Helper ◽

T Helper 1 ◽

Cell Lineages ◽

Follicular Helper ◽

Acute Viral Infection ◽

Memory Cd4 T Cells

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Sjögren’s Syndrome Minor Salivary Gland CD4+ Memory T Cells Associate with Glandular Disease Features and Have a Germinal Center T Follicular Helper Transcriptional Profile

Journal of Clinical Medicine ◽

10.3390/jcm9072164 ◽

2020 ◽

Vol 9 (7) ◽

pp. 2164 ◽

Cited By ~ 1

Author(s):

Michelle L. Joachims ◽

Kerry M. Leehan ◽

Mikhail G. Dozmorov ◽

Constantin Georgescu ◽

Zijian Pan ◽

...

Keyword(s):

T Cells ◽

Salivary Gland ◽

T Cell ◽

Differentially Expressed Genes ◽

Cd4 T Cells ◽

Memory T Cells ◽

Sjogren's Syndrome ◽

Differentially Expressed ◽

Follicular Helper ◽

Memory Cd4 T Cells

To assess the types of salivary gland (SG) T cells contributing to Sjögren’s syndrome (SS), we evaluated SG T cell subtypes for association with disease features and compared the SG CD4+ memory T cell transcriptomes of subjects with either primary SS (pSS) or non-SS sicca (nSS). SG biopsies were evaluated for proportions and absolute numbers of CD4+ and CD8+ T cells. SG memory CD4+ T cells were evaluated for gene expression by microarray. Differentially-expressed genes were identified, and gene set enrichment and pathways analyses were performed. CD4+CD45RA− T cells were increased in pSS compared to nSS subjects (33.2% vs. 22.2%, p < 0.0001), while CD8+CD45RA− T cells were decreased (38.5% vs. 46.0%, p = 0.0014). SG fibrosis positively correlated with numbers of memory T cells. Proportions of SG CD4+CD45RA− T cells correlated with focus score (r = 0.43, p < 0.0001), corneal damage (r = 0.43, p < 0.0001), and serum Ro antibodies (r = 0.40, p < 0.0001). Differentially-expressed genes in CD4+CD45RA− cells indicated a T follicular helper (Tfh) profile, increased homing and increased cellular interactions. Predicted upstream drivers of the Tfh signature included TCR, TNF, TGF-β1, IL-4, and IL-21. In conclusion, the proportions and numbers of SG memory CD4+ T cells associate with key SS features, consistent with a central role in disease pathogenesis.

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Distinct Memory CD4+ T Cells with Commitment to T Follicular Helper- and T Helper 1-Cell Lineages Are Generated after Acute Viral Infection

Immunity ◽

10.1016/j.immuni.2013.02.020 ◽

2013 ◽

Vol 38 (4) ◽

pp. 805-817 ◽

Cited By ~ 192

Author(s):

J. Scott Hale ◽

Ben Youngblood ◽

Donald R. Latner ◽

Ata Ur Rasheed Mohammed ◽

Lilin Ye ◽

...

Keyword(s):

T Cells ◽

Viral Infection ◽

Cd4 T Cells ◽

T Helper ◽

T Helper 1 ◽

Cell Lineages ◽

Follicular Helper ◽

Acute Viral Infection ◽

Memory Cd4 T Cells

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A Newly Generated DOCK8-expressing T Follicular Helper Cell Type, aiCD4 T Cell, Causes Systemic Lupus Erythematosus: Self-Organized Criticality Theory

10.21203/rs.3.rs-82784/v1 ◽

2020 ◽

Author(s):

Shunichi Shiozawa ◽

Ken Tsumiyama ◽

Keiichi Sakurai ◽

Takahiko Horiuchi ◽

Tsukasa Matsubara ◽

...

Keyword(s):

T Cells ◽

Lupus Erythematosus ◽

Cd4 T Cells ◽

Cell Type ◽

Systemic Lupus ◽

Self Organized ◽

Follicular Helper ◽

Helper Cell Type ◽

Self Organized Criticality ◽

T Follicular Helper Cell

Abstract Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease of unknown cause. We show here that a novel T follicular helper cell type expressing the guanine nucleotide exchange factor DOCK8 on the cell surface causes SLE. These cells, which we have designated autoantibody-inducing CD4 T (aiCD4 T) cells, are generated after resuscitation from anergy following strong TCR stimulation by antigen. When mice normally not prone to autoimmune disease were repeatedly immunized with an antigen such as OVA, they generated DOCK8+ CD4 T cells. These DOCK8+ CD4 T cells, in vivo and also upon transfer to naïve mice, induced a variety of autoantibodies and lesions characteristic of SLE. TCR repertoire analyses showed that a substantial number of novel TCR repertoires were generated in the DOCK8+ CD4 T cells, which induced novel autoantibodies upon transfer to naïve mice. DOCK8+ CD4 T cells are localized in splenic red pulp, the space immunoreactive against a variety of antigens, and specifically increased in the peripheral blood of SLE patients in association with disease activity. Anti-DOCK8 antibody treatment ameliorated the lesions induced by DOCK8+ CD4 T cells and in lupus model (NZB x W) F1 mice. Thus, when CD4 T cells are overstimulated by an external disturbance, i.e., repeatedly stimulated with antigen, to levels that surpass the system’s self-organized criticality, these cells express DOCK8 on the cell surface and acquire autoreactivity via TCR re-revision at the periphery. These DOCK8+ CD4 T cells subsequently induce a variety of autoantibodies and SLE.

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