Summary: A study published in Nature Immunology identifies a cellular mechanism that helps prevent autoimmune disease after infection. Researchers report that a specific population of immune cells arises during the late phase of the response to influenza and helps block the development of self-reactive antibodies.
Source: University of Alabama at Birmingham
Researchers investigate how the immune system prevents autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis following infection.
The immune system’s primary defense against viruses and bacteria is production of antibodies. Antibodies act like guided missiles, binding to invading pathogens and neutralizing them. To generate ever more effective antibodies, antibody-producing B cells undergo cycles of mutation and selection. While this process improves pathogen recognition, the random mutations can occasionally produce B cells that target the body’s own tissues, creating the risk of autoimmune disease.
André Ballesteros-Tato, Ph.D., assistant professor in the UAB Department of Medicine, compares these accidental autoimmune reactions to collateral damage in wartime: unintended and harmful side effects that can arise amid an aggressive response.
In a study published in Nature Immunology, Ballesteros-Tato and colleagues used an influenza infection model in mice to examine regulatory mechanisms that protect against such collateral autoimmune reactions. They discovered a population of immune cells that emerges during the later phase of the antiviral response. These cells, called T follicular regulatory cells (TFR cells), act in lymphoid follicles to prevent the generation and expansion of B cell variants that produce self-reactive antibodies. Importantly, the presence of TFR cells did not weaken the protective antibody response against the influenza virus.
Study details
TFR cells are less well understood than conventional regulatory T cells (Treg cells). Treg cells are known to suppress immune activity to limit damage once an infection is controlled. The UAB team found key differences in how Treg and TFR cells are regulated during influenza infection.
Interleukin-2 (IL-2) is a critical signaling molecule that increases early in the immune response and drives development of conventional Treg cells. In the mouse model, Treg cells peaked about one week after infection. Unexpectedly, the researchers found that high IL-2 levels during the peak of the response actually suppressed TFR cell development. This suppression depended on the transcriptional repressor Blimp-1, which blocks expression of the Bcl-6 master transcription factor required for the TFR cell program.
After the virus was cleared and IL-2 levels declined, a subset of Treg cells reduced their expression of CD25 (part of the IL-2 receptor). Those cells then upregulated Bcl-6 and differentiated into TFR cells, with TFR numbers peaking roughly 30 days after infection. The newly formed TFR cells migrated into B cell follicles of lymph nodes, the sites where antibody-producing B cells proliferate and undergo further mutation and selection to strengthen antibody specificity.
Within follicles, TFR cells acted to prevent the accumulation and expansion of B cell variants that had acquired self-reactivity through mutation. Experimental removal of TFR cells or interference with their development allowed expansion of B cell clones that produced anti-self antibodies, as shown by increased anti-nuclear antibody levels. Despite this containment of self-reactive clones, TFR activity did not measurably blunt the virus-specific antibody response, demonstrating a selective regulatory role that preserves protective immunity while enforcing B cell tolerance.
As the authors summarize, IL-2 signaling supports the conventional Treg cell response early in infection but, by the same mechanism, temporarily prevents TFR cell formation. Once IL-2 decreases after pathogen clearance, some Treg cells convert into TFR cells and relocate to B cell follicles where they enforce tolerance and guard against post-infectious autoimmunity.
Contributors and funding
The Nature Immunology article, “Dynamic regulation of T follicular regulatory cell responses by interleukin 2 during influenza infection,” lists Davide Botta, Michael J. Fuller, Tatiana T. Marquez-Lago, Holly Bachus, John E. Bradley, Amy S. Weinmann, Allan J. Zajac, Troy D. Randall, Frances E. Lund, Beatriz León and André Ballesteros-Tato as co-authors, with affiliations across the UAB Department of Medicine, Department of Microbiology, the UAB Informatics Institute and the Department of Genetics.
Funding and support for this research came from the University of Alabama at Birmingham and multiple National Institutes of Health grants (AI110480, AI116584, AI097357, AI109962, AI061061 and AI049360). An X-RAD 320 unit was acquired through an NIH Research Facility Improvement Grant (G20RR022807-01), and the UAB flow cytometry core received support from NIH grants AR048311 and AI027767. At UAB, Frances E. Lund holds the Charles H. McCauley Chair of Microbiology and Troy D. Randall holds the J. Claude Bennett Endowed Professorship in Rheumatology and Immunology.
Original research
Nature Immunology. Published online September 11, 2017. doi:10.1038/ni.3837
Key takeaway
This study identifies a time-dependent regulatory switch: IL-2 promotes conventional Treg cells early in infection while delaying TFR cell formation. After infection resolves and IL-2 falls, some Treg cells become TFR cells, migrate into B cell follicles, and selectively suppress self-reactive B cell clones. This mechanism helps prevent autoimmune responses after viral infections without compromising pathogen-specific immunity.