Targeting DCs to induce regulatory T cells in vivo

Dendritic cells (DCs) play a central role in controlling immune responses, as initiators of either T-cell activation or tolerance. The functional activity of DCs, and thereby the outcome of an immune response, is determined in part by their maturation state. Immature (resting or steady-state) DCs may present antigen to T cells in a tolerogenic fashion, whereas mature (activated) DCs induce T-cell activation. Steinman and Nussenzweig proposed that immature DCs are crucial to the maintenance of immunologic self-tolerance (Proc Nat Acad Sci U S A. 2002;99:351-358). Tissue damage and/or inflammation induce maturation of DCs. In an inappropriate setting, this may lead to a break in tolerance to self-antigens and activation of autoreactive T cells.

Efforts to exploit the tolerogenic potential of immature DCs are being actively pursued. Hawiger and colleagues (J Exp Med. 2001;194:769-779) were the first to use antibody to DEC-205, a DC-restricted endocytic receptor, to specifically target antigen to immature DCs for tolerance induction in vivo. Antibody bound to DEC-205 is efficiently internalized and delivered to antigen processing compartments inside the cell (along with linked protein) without inducing DC maturation.

In this issue, Mahnke and colleagues (page 4862), using anti-DEC mAb linked biochemically to ovalbumin (OVA), report that tolerance induction in vivo is associated with an increase in CD4⁺ CD25⁺ regulatory T (T_REG) cells that coexpress CTLA-4⁺. Subcutaneous injection of OVA-anti-DEC conjugates induced anergy in vitro and in vivo in OVA-specific TCR transgenic T-cells and also suppressed the OVA-specific DTH response in vivo. CTLA-4⁺ CD4⁺ CD25⁺ T_REG cells were induced exclusively in OVA-anti-DEC–treated mice. CD4⁺ CD25⁺ TCR transgenic T cells recovered from these mice actively suppressed cytokine secretion and T-cell proliferation in vitro in a dose- and cell-contact–dependent manner; their depletion restored IL-2 production and T-cell proliferation. Coinjection of anti-CD40 mAb, a potent DC-maturation stimulus, abrogated the suppression of T-cell proliferation and restored IL-2 production as well as the DTH response to OVA, confirming the importance of the DC maturation state in activation of T_REG cells and tolerance induction in vivo.

Naturally occurring CD4⁺ CD25⁺ T_REG cells, together with other immunoregulatory cells, carry out an important physiologic function: the need to balance self-recognition and reactivity with self-tolerance. Anergic T cells can manifest functional properties similar to those of natural regulatory T cells, and immature DCs have been implicated in the induction of both anergic and regulatory T cells (Jonuleit et al, Trend Immunol. 2001;22:394-400). We are just beginning to tap the potential for manipulating and using regulatory T cells in the settings of autoimmune disease, allergy, and tissue or organ transplantation. Although many questions remain to be answered, direct targeting of immature DCs, as described by Mahnke and colleagues, offers an exciting new therapeutic opportunity for their induction in vivo.