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Related Concept Videos

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Related Experiment Video

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Endogenous T Cell Receptor Rearrangement Represses Aggressive Central Nervous System Autoimmunity in a TcR-Transgenic

Asmita Pradeep Yeola1, Prenitha Mercy Ignatius Arokia Doss1, Joanie Baillargeon1

  • 1Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Quebec City, QC, Canada.

Frontiers in Immunology
|February 4, 2020
PubMed
Summary

T cell receptor (TcR) allelic inclusion is vital for generating regulatory T cells (Tregs) that suppress central nervous system (CNS) autoimmunity in experimental autoimmune encephalomyelitis (EAE). This study reveals TcR promiscuity

Keywords:
1C6EAE (experimental autoimmune encephalomyelitis)FoxP3RAGTCR transgenic miceTreg—regulatory T cellallelic exclusionnon-obese diabetic (NOD)

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Area of Science:

  • Immunology
  • Neuroimmunology
  • Autoimmunity

Background:

  • Experimental autoimmune encephalomyelitis (EAE) models multiple sclerosis (MS) immune responses.
  • 1C6 transgenic mice (NOD background) have T cell receptors (TcRs) specific for myelin oligodendrocyte glycoprotein (MOG) peptide [35-55].
  • The role of TcR allelic inclusion in shaping the TcR repertoire remains unclear.

Purpose of the Study:

  • To investigate the role of TcR allelic inclusion in T cell repertoire development and autoimmunity.
  • To determine the impact of disrupted thymic selection on EAE development.
  • To assess the contribution of regulatory T cells (Tregs) in controlling CNS autoimmunity.

Main Methods:

  • Analysis of T cell receptor (TcR) Vα chain expression in 1C6 transgenic mice.
  • Generation of 1C6 × Rag1-/- mice to enforce transgenic TcR expression.
  • Induction of EAE via MOG [35-55] immunization and passive T cell transfer experiments.
  • Assessment of FoxP3+ CD4+ T regulatory cells (Tregs) in the CNS and in vivo Treg blockade.

Main Results:

  • 1C6 T cells showed promiscuous expression of non-transgenic Vα chains.
  • Enforced transgenic TcR expression in 1C6 × Rag1-/- mice disrupted thymic negative selection, reducing mature peripheral T cells.
  • 1C6 × Rag1-/- mice developed spontaneous and severe EAE, which was partially rescued by CD4+ T cell transfer.
  • FoxP3+ CD4+ Tregs were present in the CNS of EAE-affected mice receiving CD4+ T cells, but absent in Rag1-/- mice without them.
  • Treg blockade accelerated EAE onset in 1C6 mice.

Conclusions:

  • TcR allelic inclusion is critical for generating FoxP3+ CD4+ T cells.
  • These Tregs are essential for suppressing severe central nervous system (CNS) autoimmunity in the EAE model.
  • Disruption of TcR repertoire generation impacts Treg development and autoimmune control.