Precocious Interleukin 21 Expression in Naive Mice Identifies a Natural Helper Cell Population in Autoimmune Disease
Elisabeth A. Marnik,
Xulong Wang,
Thomas J. Sproule,
Giljun Park,
Gregory J. Christianson,
Sarah Kate Lane-Reticker,
Shweta Jain,
Theodore Duffy,
Hongsheng Wang,
Gregory W. Carter,
Herbert C. Morse, III,
Derry C. Roopenian
Affiliations
Elisabeth A. Marnik
The Jackson Laboratory, Bar Harbor, ME, USA
Xulong Wang
The Jackson Laboratory, Bar Harbor, ME, USA
Thomas J. Sproule
The Jackson Laboratory, Bar Harbor, ME, USA
Giljun Park
The Jackson Laboratory, Bar Harbor, ME, USA
Gregory J. Christianson
The Jackson Laboratory, Bar Harbor, ME, USA
Sarah Kate Lane-Reticker
The Jackson Laboratory, Bar Harbor, ME, USA
Shweta Jain
Virology and Cellular Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Disease (NIAID), NIH, Rockville, MD, USA
Theodore Duffy
The Jackson Laboratory, Bar Harbor, ME, USA
Hongsheng Wang
Virology and Cellular Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Disease (NIAID), NIH, Rockville, MD, USA
Gregory W. Carter
The Jackson Laboratory, Bar Harbor, ME, USA
Herbert C. Morse, III
Virology and Cellular Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Disease (NIAID), NIH, Rockville, MD, USA
Interleukin 21 (IL-21) plays key roles in humoral immunity and autoimmune diseases. It is known to function in mature CD4+ T follicular B cell helper (TFH) cells, but its potential involvement in early T cell ontogeny is unclear. Here, we find that a significant population of newly activated thymic and peripheral CD4+ T cells functionally expresses IL-21 soon after birth. This naturally occurring population, termed natural (n)TH21 cells, exhibits considerable similarity to mature TFH cells. nTH21 cells originating and activated in the thymus are strictly dependent on autoimmune regulator (AIRE) and express high levels of NUR77, consistent with a bias toward self-reactivity. Their activation/expansion in the periphery requires gut microbiota and is held in check by FoxP3+ TREG cells. nTH21 cells are the major thymic and peripheral populations of IL-21+ cells to expand in an IL-21-dependent humoral autoimmune disease. These studies link IL-21 to T cell ontogeny, self-reactivity, and humoral autoimmunity.
