A role for dendritic cells (DCs) in autoimmunity remains to be fully delineated. In this issue of Immunity,Teichmann et al. (2010) reveal critical functions for DCs in augmenting, but surprisingly not in initiating, spontaneous autoimmune disease.
In this issue of Immunity, Teichmann et al. (2010) address this question by adopting a DC ablation model in combination with the widely used MRL.Faslpr mouse model of lupus. CD11c-DTA mice, in which CD11c-expressing cells express the diphtheria toxin α (DTA) chain, were generated previously and demonstrated an impairment of antiviral and antiparasite immunity in the virtual absence of conventional DCs (cDCs) ([Birnberg et al., 2008] and [Ohnmacht et al., 2009]). By generating such mice on the MRL.Faslpr lupus-prone background,Teichmann et al. (2010) studied the development and progression of lupus in a constitutively cDC-deficient scenario. This elegant model allows the investigation of cDC functions during the natural onset and progression of autoimmune disease. The work concludes that cDCs are crucial in regulating the magnitude of spontaneously arising autoimmune disease, with CD11c-DTA mice exhibiting less severe disease.
One of the most interesting observations in this study is that although cDCs were critical for the expansion of preactivated T cells, they were not necessary for the initial activation of T and B cells. The authors arrived at this conclusion because in CD11c-DTA lupus-prone mice, spontaneous T cell activation occurred and in fact the proportion of T cells maintaining a naive phenotype was small. This is surprising and is in stark contrast to the well-documented function of cDCs as the primary cell type capable of priming naive T cell responses during infection, by use of this and other ablation systems ([Birnberg et al., 2008], [Jung et al., 2002] and[Ohnmacht et al., 2009]). Nevertheless, Teichmann et al. (2010) do demonstrate that activated T cells are reduced in cDC-deficient animals, albeit modestly (Figure 1). In addition, T helper 1 cell differentiation and IFN-γ production were attenuated in cDC-deficient animals. This finding is not entirely unprecedented as it was demonstrated previously that lymph node CD4+ T cell responses to a model antigen remained intact independently of cDCs in CD11c-DTA mice (Birnberg et al., 2008). Furthermore, spontaneous autoimmunity developed in CD11c-DTA mice generated by one group (Ohnmacht et al., 2009), but not another (Birnberg et al., 2008), and this was associated with an increased frequency of activated (CD44hiCD62Llo) CD4+ T cells. For further elucidation of the contribution of autoreactive T cells to the activated T cell pool in CD11c-DTA mice, it would also be interesting to compare naive and activated T cell subset ratios in the CD11c-DTA colony that does not develop autoimmunity. The discrepancies between studies in CD11c-DTA mouse strains suggest a role of cDCs in autoimmunity that depends on environmental conditions and/or genetic background ([Birnberg et al., 2008] and [Ohnmacht et al., 2009]). There are also differences in DC deletion between different CD11c-DTA strains. In the CD11c-DTA colony that develops autoimmunity and in the CD11c-DTA lupus-prone mice, plasmacytoid DCs and Langerhans cells are ablated, whereas these remained present in the colony generated by Jung and colleagues ([Birnberg et al., 2008] and [Ohnmacht et al., 2009]).
Because CD11c+ cells are efficiently and constitutively deleted in the present study by Teichmann et al. (2010), the data suggest that antigen-presenting cells that lack high amounts of CD11c expression can initiate T cell responses in an autoimmune setting. In direct contrast to this conclusion, however, another study recently demonstrated a key role for cDCs in the breach of self-tolerance in another autoimmune model by using the conditional CD11c-diptheria toxin receptor (DTR) DC ablation approach (Benson et al., 2010). Because these two investigations employed different models of autoimmunity and different DC ablation systems that are known to affect myeloid populations differently (e.g., one is constitutive whereas the other transiently depletes DCs) (Bar-On and Jung, 2010), it is unclear whether the nature of the ablation model or the autoimmune disease itself accounts for the disparate outcomes. Undoubtedly, establishing a comprehensive understanding of the role of DCs in initiating autoimmune responses will require further work in multiple models of DC ablation and autoimmune disease. Caveats do exist with the CD11c-DTA system; for example, the Itgaxgene shows activity in non-DCs, including some T cells, NK cells, plasmablasts, and macrophages (Bar-On and Jung, 2010). In addition, very small numbers of residual CD11chi DCs remain in these mice, although the authors make a compelling case that residual DCs would not likely be sufficient to account for retention of T cell activation in CD11c-DTA MRL.Faslpr mice. Furthermore, in contrast to the conditional CD11c-DTR system, constitutive ablation of DCs from early development may allow formation of compensatory pathways. Importantly, these and other authors have excluded a potential role of impaired negative selection in the thymus (Birnberg et al., 2008); however, central tolerance is impaired in the CD11c-DTA mouse colony that develops spontaneous autoimmunity (Ohnmacht et al., 2009).
It will be interesting in the future, when less toxic systems than CD11c-DTR mice become available, to use a conditional DC ablation system to allow the role of DCs at distinct stages of disease progression in lupus to be dissected. Another interesting question is the role of lymphoid versus nonlymphoid organ DCs in augmenting autoreactive responses. Teichmann et al. (2010) show that although DC ablation in the kidneys was effective, lymphocytic infiltrates were still present and suggest that nonlymphoid DCs may drive in situ expansion of these infiltrates. In addition, an exciting next step would be to identify the cells responsible for priming autoreactive T and B cells in the cDC-deficient situation. Previous studies by the same group have demonstrated that the antigen-presenting functions of B cells are critical for T cell activation in MRL.Faslprmice. Consistent with this, the proportion of T cells that maintain a naive phenotype is much greater in B cell-deficient Fas-intact MRL/+ mice. However, it also remains possible that macrophages and/or other monocyte-derived cells may perform this function in the absence of CD11chi cDCs.
Although the initiation of autoimmunity did not depend on DCs, Teichmann et al. (2010) observed a marked depletion of plasmablasts and autoantibodies in CD11c-DTA MRL.Faslpr mice. DCs clearly impact antibody responses in an indirect fashion via their role in T cell priming. However, work here and by other investigators suggest that direct DC-B interactions, taking place outside the B cell follicle, may also be important (Qi et al., 2006). DCs possess nondegradative pathways for antigen that enables presentation of native antigen to the B cell receptor (Bergtold et al., 2005). Teichmann et al. (2010) show that while T cell activation occurs, short-lived plasmablasts, which originate in extrafollicular areas of the lymph node, are reduced in DC-depleted mice (Figure 1). Plasmablasts represent a major source of autoantibodies in MRL.Faslpr mice, and further, class switching of autoantibodies is reduced in the absence of cDCs. Consistent with this, autoantibody titers are reduced in the absence of cDCs, but serum Ig titers are unchanged. One caveat is that plasmablasts express CD11c and can be deleted in CD11c-DTR mice upon diptheria toxin treatment (Bar-On and Jung, 2010). Thus, it remains possible that the loss of plasmablasts in CD11c-DTA MRL.Faslpr mice is not the result of deficiency in DCs but rather a direct depletion of plasmablasts. However, the idea that DCs may regulate the differentiation of plasmablasts is consistent with previous studies on human cells by Pascual and Banchereau in which plasmacytoid DCs participated critically in the generation of plasmablasts in vitro by providing type I interferon and other cytokine support (Jego et al., 2003). Teichmann et al. (2010) rightfully point out that a key future direction will be to delineate the distinct role that plasmacytoid DCs play in this model of autoimmunity compared with the role of other DC subsets.
Finally, the authors also show that numbers of Treg cells are reduced in the absence of cDCs because of both reduced expansion and survival. In contrast, in both colonies of CD11c-DTA mice, Treg cell numbers were reported to be normal ([Birnberg et al., 2008] and [Ohnmacht et al., 2009]). However, it has been demonstrated previously that inducible depletion of DCs results in a reduction in Treg cells and an increased risk of developing autoimmunity (Darrasse-Jeze et al., 2009). Thus, the role of DCs in maintaining Treg cell numbers remains controversial, with discrepancies probably reflecting differences in the ablation strategies being used. Even in studies wherein Treg numbers were not reduced, it remains possible that alterations in the Treg cell repertoire in terms of antigen specificity and/or subset composition existed. Although it is clear from the recently growing literature on the role of DCs in autoimmunity that we still have much to learn and resolve in the area, the exciting findings provided here by Teichmann et al. provide affirmative support for important and practical concepts: DCs appear to be genuine therapeutic targets in autoimmune disorders, and inhibition of their function or numbers during ongoing, established disease may prove to be beneficial.
Benson et al., 2010 R.A. Benson, A. Patakas, P. Conigliaro, C.M. Rush, P. Garside, I.B. McInnes and J.M. Brewer, J. Immunol. 184 (2010), pp. 6378–6385. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (2)
Birnberg et al., 2008 T. Birnberg, L. Bar-On, A. Sapoznikov, M.L. Caton, L. Cervantes-Barragan, D. Makia, R. Krauthgamer, O. Brenner, B. Ludewig and D. Brockschnieder et al., Immunity 29 (2008), pp. 986–997. Article | PDF (1172 K) | View Record in Scopus | Cited By in Scopus (21)
Darrasse-Jeze et al., 2009 G. Darrasse-Jeze, S. Deroubaix, H. Mouquet, G.D. Victora, T. Eisenreich, K.H. Yao, R.F. Masilamani, M.L. Dustin, A. Rudensky, K. Liu and M.C. Nussenzweig, J. Exp. Med. 206 (2009), pp. 1853–1862. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (34)
Jego et al., 2003 G. Jego, A.K. Palucka, J.P. Blanck, C. Chalouni, V. Pascual and J. Banchereau, Immunity 19(2003), pp. 225–234. Article | PDF (286 K) | View Record in Scopus | Cited By in Scopus (305)
Jung et al., 2002 S. Jung, D. Unutmaz, P. Wong, G. Sano, K. De los Santos, T. Sparwasser, S. Wu, S. Vuthoori, K. Ko and F. Zavala et al., Immunity 17 (2002), pp. 211–220. Article | PDF (289 K) | View Record in Scopus | Cited By in Scopus (612)
Ohnmacht et al., 2009 C. Ohnmacht, A. Pullner, S.B. King, I. Drexler, S. Meier, T. Brocker and D. Voehringer,J. Exp. Med. 206 (2009), pp. 549–559. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (56)
Teichmann et al., 2010 L.L. Teichmann, M.L. Ols, M. Kashgarian, B. Reizis, D.H. Kaplan and M.J. Shlomchik,Immunity 33 (2010), pp. 967–978 this issue. Article | PDF (1593 K) | View Record in Scopus | Cited By in Scopus (1)