Dynamic regulation of T follicular regulatory cell responses by interleukin 2 during influenza infection

• Published in: Nature immunology Vol. 18; no. 11; pp. 1249 - 1260
• Main Authors: Botta, Davide, Fuller, Michael J, Marquez-Lago, Tatiana T, Bachus, Holly, Bradley, John E, Weinmann, Amy S, Zajac, Allan J, Randall, Troy D, Lund, Frances E, León, Beatriz, Ballesteros-Tato, André
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-11-2017; Nature Publishing Group
• Subjects: 13; 13/31; 13/51; 631/250/127/1213; 631/250/2152/1566/2493; Analysis; Animals; Bcl protein; Bcl-6 protein; Biomedicine; Care and treatment; CD25 antigen; Cell Movement - genetics; Cell Movement - immunology; Cytokines; Diagnosis; Follicles; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - immunology; Forkhead Transcription Factors - metabolism; Foxp3 protein; Gene Expression Profiling - methods; Host-Pathogen Interactions - drug effects; Host-Pathogen Interactions - immunology; Immune response; Immunology; Infections; Infectious Diseases; Influenza; Interleukin 2; Interleukin-2 - administration & dosage; Interleukin-2 - metabolism; Interleukin-2 - pharmacology; Interleukin-2 Receptor alpha Subunit - genetics; Interleukin-2 Receptor alpha Subunit - metabolism; Interleukins; Lymphocytes B; Lymphocytes T; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Orthomyxoviridae - immunology; Orthomyxoviridae - physiology; Orthomyxoviridae Infections - immunology; Orthomyxoviridae Infections - metabolism; Orthomyxoviridae Infections - virology; Positive Regulatory Domain I-Binding Factor 1; Proto-Oncogene Proteins c-bcl-6 - genetics; Proto-Oncogene Proteins c-bcl-6 - metabolism; T cell receptors; T-Lymphocytes, Helper-Inducer - drug effects; T-Lymphocytes, Helper-Inducer - immunology; T-Lymphocytes, Helper-Inducer - metabolism; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Transcription Factors - genetics; Transcription Factors - immunology; Transcription Factors - metabolism
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni.3837

Humoral immunity is necessary for controlling viral infection. Ballesteros-Tato and colleagues show that development of follicular regulatory T cells is prevented by high concentrations of interleukin 2 at the peak of viral infection, but resumes at later time points to suppress autoantibody production.
Interleukin 2 (IL-2) promotes Foxp3
+
regulatory T (T
reg
) cell responses, but inhibits T follicular helper (T
FH
) cell development. However, it is not clear how IL-2 affects T follicular regulatory (T
FR
) cells, a cell type with properties of both T
reg
and T
FH
cells. Using an influenza infection model, we found that high IL-2 concentrations at the peak of the infection prevented T
FR
cell development by a Blimp-1-dependent mechanism. However, once the immune response resolved, some T
reg
cells downregulated CD25, upregulated Bcl-6 and differentiated into T
FR
cells, which then migrated into the B cell follicles to prevent the expansion of self-reactive B cell clones. Thus, unlike its effects on conventional T
reg
cells, IL-2 inhibits T
FR
cell responses.