MyD88 signaling in T cells is critical for effector CD4 T cell differentiation following a transitional T follicular helper cell stage

Rajakumar Mandraju, Aakanksha Jain, Yajing Gao, Zhiming Ouyang, Michael V Norgard, Chandrashekhar Pasare

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Activation of CD4 T cells by dendritic cells leads to their differentiation into various effector lineages. The nature of the effector lineage is determined by the innate cues provided by dendritic cells to newly primed T cells. Although the cytokines necessary for several effector lineages have been identified, the innate cues that drive T follicular helper (Tfh) lineage cell development remain unclear. Here we found that following priming, CD4 T cells undergoing clonal expansion acquire a transient Tfh-like phenotype before differentiating into other effector lineages. In addition, we found that T cell-intrinsic myeloid differentiation antigen 88 (MyD88) signaling, which occurs downstream of interleukin-1 (IL-1) and IL-18 receptors, is critical for the primed CD4 T cells to transition out of the temporary Tfh lineage. Mice with T cell-specific deletion of MyD88 have a higher proportion of Tfh cells and germinal center (GC) B cells. These exaggerated Tfh cell and GC B cell responses, however, do not lead to protective immunity against infections. We demonstrate that T cellintrinsic MyD88 is critical for effector lineage differentiation as well as production of the cytokines that are necessary for class switching. Overall, our study establishes that following priming and clonal expansion, CD4 T cells undergo a transitional Tfhlike phase and that further differentiation into effector lineages is dictated by T cellintrinsic MyD88-dependent cues.

Original languageEnglish (US)
Article numbere00791-17
JournalInfection and Immunity
Volume86
Issue number5
DOIs
StatePublished - May 1 2018

Fingerprint

Differentiation Antigens
Helper-Inducer T-Lymphocytes
Cell Differentiation
T-Lymphocytes
Cues
Germinal Center
Dendritic Cells
Interleukin-18 Receptors
B-Lymphocytes
Immunoglobulin Class Switching
Cytokines
Interleukin-1
Immunity
Phenotype
Infection

Keywords

  • Borrelia burgdorferi
  • Effector T cells
  • Germinal centers
  • IL-1
  • IL-18
  • MyD88
  • Tfh cells
  • Th1/Th17 responses

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

Cite this

MyD88 signaling in T cells is critical for effector CD4 T cell differentiation following a transitional T follicular helper cell stage. / Mandraju, Rajakumar; Jain, Aakanksha; Gao, Yajing; Ouyang, Zhiming; Norgard, Michael V; Pasare, Chandrashekhar.

In: Infection and Immunity, Vol. 86, No. 5, e00791-17, 01.05.2018.

Research output: Contribution to journalArticle

@article{b3402af6f55648eda356021568ae2076,
title = "MyD88 signaling in T cells is critical for effector CD4 T cell differentiation following a transitional T follicular helper cell stage",
abstract = "Activation of CD4 T cells by dendritic cells leads to their differentiation into various effector lineages. The nature of the effector lineage is determined by the innate cues provided by dendritic cells to newly primed T cells. Although the cytokines necessary for several effector lineages have been identified, the innate cues that drive T follicular helper (Tfh) lineage cell development remain unclear. Here we found that following priming, CD4 T cells undergoing clonal expansion acquire a transient Tfh-like phenotype before differentiating into other effector lineages. In addition, we found that T cell-intrinsic myeloid differentiation antigen 88 (MyD88) signaling, which occurs downstream of interleukin-1 (IL-1) and IL-18 receptors, is critical for the primed CD4 T cells to transition out of the temporary Tfh lineage. Mice with T cell-specific deletion of MyD88 have a higher proportion of Tfh cells and germinal center (GC) B cells. These exaggerated Tfh cell and GC B cell responses, however, do not lead to protective immunity against infections. We demonstrate that T cellintrinsic MyD88 is critical for effector lineage differentiation as well as production of the cytokines that are necessary for class switching. Overall, our study establishes that following priming and clonal expansion, CD4 T cells undergo a transitional Tfhlike phase and that further differentiation into effector lineages is dictated by T cellintrinsic MyD88-dependent cues.",
keywords = "Borrelia burgdorferi, Effector T cells, Germinal centers, IL-1, IL-18, MyD88, Tfh cells, Th1/Th17 responses",
author = "Rajakumar Mandraju and Aakanksha Jain and Yajing Gao and Zhiming Ouyang and Norgard, {Michael V} and Chandrashekhar Pasare",
year = "2018",
month = "5",
day = "1",
doi = "10.1128/IAI.00791-17",
language = "English (US)",
volume = "86",
journal = "Infection and Immunity",
issn = "0019-9567",
publisher = "American Society for Microbiology",
number = "5",

}

TY - JOUR

T1 - MyD88 signaling in T cells is critical for effector CD4 T cell differentiation following a transitional T follicular helper cell stage

AU - Mandraju, Rajakumar

AU - Jain, Aakanksha

AU - Gao, Yajing

AU - Ouyang, Zhiming

AU - Norgard, Michael V

AU - Pasare, Chandrashekhar

PY - 2018/5/1

Y1 - 2018/5/1

N2 - Activation of CD4 T cells by dendritic cells leads to their differentiation into various effector lineages. The nature of the effector lineage is determined by the innate cues provided by dendritic cells to newly primed T cells. Although the cytokines necessary for several effector lineages have been identified, the innate cues that drive T follicular helper (Tfh) lineage cell development remain unclear. Here we found that following priming, CD4 T cells undergoing clonal expansion acquire a transient Tfh-like phenotype before differentiating into other effector lineages. In addition, we found that T cell-intrinsic myeloid differentiation antigen 88 (MyD88) signaling, which occurs downstream of interleukin-1 (IL-1) and IL-18 receptors, is critical for the primed CD4 T cells to transition out of the temporary Tfh lineage. Mice with T cell-specific deletion of MyD88 have a higher proportion of Tfh cells and germinal center (GC) B cells. These exaggerated Tfh cell and GC B cell responses, however, do not lead to protective immunity against infections. We demonstrate that T cellintrinsic MyD88 is critical for effector lineage differentiation as well as production of the cytokines that are necessary for class switching. Overall, our study establishes that following priming and clonal expansion, CD4 T cells undergo a transitional Tfhlike phase and that further differentiation into effector lineages is dictated by T cellintrinsic MyD88-dependent cues.

AB - Activation of CD4 T cells by dendritic cells leads to their differentiation into various effector lineages. The nature of the effector lineage is determined by the innate cues provided by dendritic cells to newly primed T cells. Although the cytokines necessary for several effector lineages have been identified, the innate cues that drive T follicular helper (Tfh) lineage cell development remain unclear. Here we found that following priming, CD4 T cells undergoing clonal expansion acquire a transient Tfh-like phenotype before differentiating into other effector lineages. In addition, we found that T cell-intrinsic myeloid differentiation antigen 88 (MyD88) signaling, which occurs downstream of interleukin-1 (IL-1) and IL-18 receptors, is critical for the primed CD4 T cells to transition out of the temporary Tfh lineage. Mice with T cell-specific deletion of MyD88 have a higher proportion of Tfh cells and germinal center (GC) B cells. These exaggerated Tfh cell and GC B cell responses, however, do not lead to protective immunity against infections. We demonstrate that T cellintrinsic MyD88 is critical for effector lineage differentiation as well as production of the cytokines that are necessary for class switching. Overall, our study establishes that following priming and clonal expansion, CD4 T cells undergo a transitional Tfhlike phase and that further differentiation into effector lineages is dictated by T cellintrinsic MyD88-dependent cues.

KW - Borrelia burgdorferi

KW - Effector T cells

KW - Germinal centers

KW - IL-1

KW - IL-18

KW - MyD88

KW - Tfh cells

KW - Th1/Th17 responses

UR - http://www.scopus.com/inward/record.url?scp=85045905880&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85045905880&partnerID=8YFLogxK

U2 - 10.1128/IAI.00791-17

DO - 10.1128/IAI.00791-17

M3 - Article

C2 - 29507085

AN - SCOPUS:85045905880

VL - 86

JO - Infection and Immunity

JF - Infection and Immunity

SN - 0019-9567

IS - 5

M1 - e00791-17

ER -