Spontaneous Autoreactive Memory B Cell Formation Driven by a High Frequency of Autoreactive CD4+ T Cells

• Published in: The Journal of immunology (1950) Vol. 178; no. 8; pp. 4793 - 4802
• Main Authors: Guay, Heath M, Larkin, Joseph, III, Picca, Cristina Cozzo, Panarey, Laura, Caton, Andrew J
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15-04-2007
• Subjects: Amino Acid Sequence; Animals; Autoantibodies - biosynthesis; B-Lymphocytes - physiology; CD4-Positive T-Lymphocytes - physiology; Hemagglutinin Glycoproteins, Influenza Virus - immunology; Immunization; Immunologic Memory; Mice; Mice, Inbred BALB C; Mice, Transgenic; Molecular Sequence Data; T-Lymphocytes, Regulatory - physiology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.178.8.4793

Although somatically mutated autoantibodies are characteristic of many autoimmune diseases, the processes that can lead to their development remain poorly understood. We have examined the formation of autoreactive memory B cells in PevHA mice, which express the influenza virus PR8 hemagglutinin (HA) as a transgenic membrane bound neo-self-Ag. Using a virus immunization strategy, we show that PR8 HA-specific memory B cell formation can occur in PevHA mice, even though a major subset of PR8 HA-specific B cells is negatively selected from the primary repertoire. Moreover, PR8 HA-specific memory B cells develop spontaneously in TS1 x PevHA mice, which coexpress a transgenic PR8 HA-specific TCR and contain a high frequency of HA-specific CD4(+) T cells. Notably, autoreactive memory B cell formation occurred in TS1 x PevHA mice even though approximately half of the HA-specific CD4(+) T cells were CD25(+)Foxp3(+) cells that could significantly attenuate, but did not completely abolish HA-specific autoantibody production in an adoptive transfer setting. The findings provide evidence that a high frequency of autoreactive CD4(+) T cells can be sufficient to promote autoreactive memory B cell formation in the absence of signals provided by overt immunization or infection and despite the presence of abundant autoantigen-specific CD4(+)CD25(+)Foxp3(+) regulatory T cells.