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Spontaneous Autoreactive Memory B Cell Formation Driven by a High Frequency of Autoreactive CD4⁺ T Cells¹

Wistar Institute, Philadelphia, PA 19104

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by AI59166, AI24541, and CA09140 from the National Institutes of Health, by the Lupus Foundation of Southeastern Pennsylvania, and by the Commonwealth Universal Research Enhancement Program, Pennsylvania Department of Health.

² Current address: Inflammation, Wyeth Research, Cambridge, MA 02140.

³ Address correspondence and reprint requests to Dr. Andrew J. Caton, Wistar Institute, Room 262, 3601 Spruce Street, Philadelphia, PA 19104. E-mail address: caton{at}wistar.org

⁴ Abbreviations used in this paper: HA, hemagglutinin; HAU, hemagglutinating unit; Tg, transgenic; BM, bone marrow; ASC, Ab-secreting cell; HI, HA inhibition.