Direct DC hit activates T_Reg cells

Delivering antigen directly to immature dendritic cells (DCs) in lymphoid tissues might be an effective way of activating regulatory T (T_Reg) cells according to a recent study published in Blood.

The idea that steady-state antigen presentation by immature or resting DCs leads to immune tolerance is an attractive hypothesis, but it is difficult to test. Evidence in support of this model has come from studies showing that antibodies specific for the lymphoid DC marker CD205 (also known as DEC205) can target antigens specifically to DCs in vivo. CD205, a C-type lectin, is involved in the uptake of antigen into the MHC class II antigen-processing/presentation pathway. Previously, Ralph Steinman, Michel Nussenzweig and colleagues had shown that injection of a modified CD205-specific monoclonal antibody containing an ovalbumin (OVA) peptide resulted in antigen presentation by DCs and OVA-specific T-cell tolerance. But, the mechanism of tolerance was not clear.

In this new study, Karsten Mahnke and co-workers conjugated a CD205-specific antibody to OVA protein and injected it into mice containing OVA-specific T-cell-receptor-transgenic CD4⁺ T cells. Eight days later, OVA-specific T cells were stimulated in vitro with OVA-pulsed DCs, but they failed to proliferate or secrete interleukin-2 (IL-2). Approximately 20% of these T cells had an increased level of expression of the T_Reg-cell-associated markers CD25 and cytotoxic T-lymphocyte antigen 4 (CTLA4).

So, does this minor CD25⁺CTLA4⁺ population suppress the function of the other T cells? When the OVA-specific T cells recovered from mice injected with the OVA–CD205-specific antibody were depleted of CD25⁺ cells, IL-2 production and proliferation in vitro were restored. Moreover, these CD25⁺ cells were capable of suppressing the proliferation of T cells in a mixed leukocyte reaction, whereas OVA-specific CD25⁺ T cells from control mice had no effect. This indicates that the T_Reg cells are induced in vivo and that their effects are antigen nonspecific.

The authors conclude that antigen presentation by immature DCs in vivo can lead to the activation of T_Reg cells. But, the importance of these cells to the tolerance that is induced by CD205-targeted antigen in vivo remains to be investigated.