Simultaneous Induction of CD4 T Cell Tolerance and CD8 T Cell Immunity by Semimature Dendritic Cells

Abstract

Previous studies suggested that depending on their maturation state, dendritic cells (DC) could either induce T cell tolerance (immature and semimature DC) or T cell activation (mature DC). Pretreatment of C57BL/6 mice with encephalitogenic myelin oligodendrocyte glycoprotein (MOG)35–55 peptide-loaded semimature DC protected from MOG-induced autoimmune encephalomyelitis. This protection was mediated by IL-10-producing CD4 T cells specific for the self Ag. Here we show that semimature DC loaded with the MHC class II-restricted nonself peptide Ag (OVA) induce an identical regulatory T cell cytokine pattern. However, semimature DC loaded simultaneously with MHC class II- and MHC class I-restricted peptides, could efficiently initiate CD8 T cell responses leading to autoimmune diabetes in a TCR-transgenic adoptive transfer model. Double-peptide-loaded semimature DC also induced simultaneously in the same animal partially activated CD8 T cells with cytolytic function as well as protection from MOG-induced autoimmune encephalomyelitis. Our study suggests that the decision between tolerance and immunity not only depends on the DC, but also on the type and activation requirements of the responding T cell.

Semi‐mature DC are immunogenic and not tolerogenic when inoculated at a high dose in collagen‐induced arthritis mice

“…However, some reports have demonstrated that DC are able to induce not only immunity but also immune tolerance, depending on the stage of their maturation. In fact, some papers have demonstrated that certain types of DC have potential for the treatment of autoimmune diseases [6,7,30]. Our results also indicated that TNF-a-mediated smDC might be applicable to the RA treatment at least in animal models, and this claim was further supported by our detailed analysis of smDC-mediated immune reactions both in vitro and in vivo.…”

“…The natural function of immature DC (iDC) is to create conditions for self-tolerance either via the generation of Treg or via the induction of apoptosis or anergy of autoreactive effector cells [4,5]. Moreover, some reports have demonstrated that tolerance is observed when partial-or semi-maturation of DC (semi-mature DC, smDC) occurs, whereas only fully matured DC (mDC) are immunogenic [6,7]. It has also been reported that in vitro-generated smDC, which were matured by TNF-a and intravenously injected into mice, functioned in a tolerogenic fashion via the prevention of Th1-dependent EAE, by inducing CD4…”

Dendritic Cell Differentiation State and Their Interaction with NKT Cells Determine Th1/Th2 Differentiation in the Murine Model ofLeishmania majorInfection

“…To date the tolerogenic capacity of TNF-DCs has also been shown in other autoimmune diseases like thyroiditis and rheumatoid arthritis (17,18). However, TNF-DCs pulsed simultaneously with MHC II-and MHC I-restricted peptides efficiently initiate CD8 T cell responses leading to autoimmune diabetes, despite the simultaneous induction of a protective IL-10-secreting CD4 ϩ T cell response (19). Thus, more detailed analyses regarding the immune response induced by TNF-DCs are needed.…”

Role of innate immunity in tolerance induction

“…Однако дальнейшие исследования показали, что TNF-ДК, нагруженные одновременно пептидами, ограниченными MHC I и MHC II, делали толерантными Т-клетки CD4+, но не Т-клетки CD8 + . Прайминг Т-клеток CD8+ TNF-ДК был достаточен для индукции экспериментального аутоиммунного диабета [145]. Более того, подобно незрелым ДК, TNF-ДК не окончательно дифференцировались и могли становиться иммуностимуляторными в ответ на дальнейшую активацию сигналами созревания ДК [65,146].…”