Effects of TGFbeta on B cells of vaccinated NOD mice are dependent on costimulation via CD40: role for inhibitory Smads?

TC Martins, PhDa, AP Águas, MD, PhDa,b

a Institute for Molecular and Cell Biology, Porto, Portugal Portugal bAbel Salazar Institute for the Biomedical Sciences, University of Porto, Porto, Portugal.

IDDM of NOD mice may be prevented by mycobacterial infection. This is associated with increased Treg cells. We now quantified secretion of Treg cytokines (IL-10 and TGFb and analysed effects of increased TGFb on B cells from infected and control mice. Diabetes prevention is associated with increased levels of TGFb and IL-10. The effects of TGFb on CD40 expression are dependent on the stimuli to which the cells were submitted: it decreases CD40 expression on cells stimulated with LPS or LPS+anti-CD40; CD40 expression is increased if cells are exposed to antigen. TGFb effects also depend on the origin of cells. TGFb reduces the formation of blasts of control mice in response to mitogen and antigen; the effect of TGFb on LPS-induced blast formation may be rescued by CD40 stimulation; in contrast, co-activation of B cells via CD40 further decreases blast formation in response to antigen. As for cells of infected mice, TGFb does not reduce blast formation. Regarding B-cell subsets in culture, TGFb opposes the effects of different treatments; changes are dependent on CD40 costimulation of cells. Thus, vaccination against diabetes is associated with secretion of Treg cytokines. TGFb decreases proliferation of B cells and induces changes in B-cell subsets, which are dependent on CD40 costimulation. This may be due to regulation of expression of inhibitory Smads (Smad7/6). The ability of TGFb to alter CD40 expression on B cells may constitute a mechanism through which TGFb originates optimal conditions to exert immunosuppression. This work was supported by grants from FCT/FEDER/POCTI.

KEY WORDS: Autoimmune diabetes, Treg cells, TGF-beta, Smad7 B cells.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Immunotherapy.