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The role of complement in transcriptional Th2 programming of pulmonary dendritic cells in allergic asthma

Pulmonary dendritic cells (DC) are necessary and sufficient to drive maladaptive Th2 and/or Th17 immune response in response to allergens. Under steady state conditions, the lung harbors several dendritic cell subsets, comprising CD103+ and CD11b+ conventional DCs (cDCs), monocyte-derived DCs (moDCs) and plasmacytoid DCs (pDC). Several reports suggest that CD11b+DC and moDCs contribute to Th2/Th17 development, whereas CD103+cDCs and pDCs promote tolerance. Although several phenotypic markers have been described,  they do not allow a definite discrimination of the first two subsets. Recently, critical parts of a genetic program have been identified in CD11b+DCs that drive Th2 differentiation. More specifically, the transcription factors IRF4 and STAT5 have been found to play critical roles in pulmonary Th2 programming. Both of them result in promoting the Th2 differentiation signaling through different pathways. It is also known that in response to allergens the complement system is activated and generate the anaphylatoxins (AT) C3a and C5a, which signal through C3aR, C5aR1 and C5aR2. These AT/AT receptors have been shown to play a major role in the development of Th2/Th17 immune responses. However, until now it remains unclear how the ATs regulate the programming of DCs into a phenotype that drives Th2 immune responses in allergic asthma

The Köhl lab has a longstanding interest in the role of complement in the development of allergic asthma. Using adoptive transfer of BMDCs, we have shown that the C5a/C5aR1 axis on DCs drive the induction of Th2 immune responses [Schmudde et al. Mucosal Immunol 2013; Engelke et al. J. Immunol 2014). Using a novel GFP-C5aR1 reporter mouse, we found that pulmonary CD11b+ cDCs and moDCs but not CD103+ cDCs express C5aR1 [Karsten et al. J. Immunol. 2015]. Finally, we observed a strong impact of the C5a/C5aR1 axis on TLR-driven IL-12 family cytokine production in macrophages [Hawlisch et al. Immunit  2005], DCs [Weaver et al. Eur. J. Immunol. 2010] and monocytes [Reis et al. Brain Behav. Immunol 2011]. More recently, we showed that CD11b+ cDCs  are heterogeneous and comprise C5aR1+ and C5aR1- subpopulations, which differ in their potency to drive CD4+ T cell proliferation. C5aR1-CD11b+ cDCs from either WT or C5aR1-/- mice are significantly more potent to induce T cell proliferation than their C5aR1+ counterparts (Figure 1). Taken together, our findings suggest that the C5a/C5aR1 axis activation on CD11b+ cDCs drives the activation of allergen-specific CD4+ T cells during initial antigen encounter.

This project aims to define the molecular mechanisms, by which local C5a generationin the lung and specific activation of C5aR1 on pulmonary CD11b+ cDCs controls airway tolerance and protects from undesired CD4+ T cell activation by potential allergens such as house-dust mite.  

Figure 1: CD11b+ cDC-induced T cell proliferation. WT and C5aR1-/- mice were treated once with HDM/OVA (100 µg/40 µg) i.t. (A) C5aR1/CD88+and CD88-CD11b+ cDCs from WT and CD88-CD11b+cDCs from C5aR1-/- mice were purified from lung tissue by FACS 24h after the treatment, For 4 days, they were co-cultured with CFSE-labeled CD4+ T cells in presence of OVA (40 µg/ml) and CSF-2 (20 ng/ml). Grey histogram = FMO control; solid line = WT CD11b+ cDCs; dashed line = C5aR1-/- CD11b+cDCs. (B) At day 4 of the co-culture, the T cell proliferation was determined evaluating the intensity of the CFSE signal by flow cytometry. Grey histogram = T cells unstimulated; green line = WT CD88+CD11b+cDCs; blue line = WT CD88–CD11b+ cDCs; red line = C5aR1-/- CD88-CD11b+cDCs. (C) Shown is the frequency of proliferated T cells as mean ± SEM, n = 3 per group, * p < 0.05.

References

  1. Karp C.L., Gruppe A., Schadt E., Ewart S.L., Keane-More M., Cuomo P.J., Köhl J., Wahl L., Kupermann D., Germer S., Aud D., Peltz G., Wills-Karp M. Identification of complement factor 5 (C5) as a susceptibility locus for experimental allergic asthma. 2000 Nat. Immunol. 3: 221 - 226.
  2. Hawlisch H., Belkaid Y., Bälder R., Hildeman, D., Köhl J.. C5a negatively regulates Toll-like receptor 4-induced immune responses. 2005 Immunity, 22: 415-426.
  3. Lewkowich IP, Herman NS, Schleifer KW, Dance MP, Chen BL, Dienger KM, Sproles AA, Shah JS, Köhl J, Belkaid Y, Wills-Karp M. CD4+CD25+ T cells protect against experimentally induced asthma and alter pulmonary dendritic cell phenotype and function. 2005 J. Exp. Med. 202: 1549-1561.
  4. Köhl J., Bälder R., Lewkowich I., Pandey M.K., Hawlisch H., Wang L., Herman N., Sproles A., Best J., Zwirner J., Lambris J.D., Whitsett J.D., and Wills-Karp M.. A regulatory role for the C5a anaphylatoxin on type 2 immunity in asthma. 2006 J. Clin. Invest. 116: 783-796.
  5. Zhang X., Lewkowich I.P., Köhl G., Clark J.F., Wills-Karp M., Köhl J. A protective role for C5a in the development of allergic asthma associated with altered levels of B7-H1 and B7-DC on plasmacytoid dendritic cells. 2009 J. Immunol. 182: 5123-5130.
  6. Weaver DJ, Reis E.S., Pandey M.K., Köhl, G., Harris, N., Gerard C., Köhl, J. C5a receptor-deficient dendritic cells promote induction of Treg and Th17 cells. 2010. Eur J. Immunol. 40: 710-721.
  7. Reis S. E., Lange T., Köhl G., Hermann A., Tschukalow A.V., Naujoks J., Born J., Köhl J. Sleep and circadian rhythm regulate circulating complement factors and immunoregulatory properties of C5a. Brain Behav. Immun. 2011 25:1416-1426.
  8. Schmudde I., Ströver, J.A., Vollbrandt T., König P., Karsten C.M., Laumonnier Y., Köhl J. C5a receptor signaling in dendritic cells controls the development of maladaptive Th2 and Th17 immunity in experimental allergic asthma. 2013 Mucosal Immunol. 6:807-825. 
  9. Engelke C., Wiese A., Schmudde I., Ender F., Ströver H.A., Vollbrandt T., König P., Laumonnier Y., Köhl J.. Distinct roles of the anaphylatoxins C3a and C5a in dendritic cell-mediated allergic asthma. 2014 J. Immunol 193: 5387-5401.
  10. Karsten C.M., Laumonnier Y., Eurich B., Ender F., Bröker K., Roy S., Czabanska A., Vollbrandt T., Figge J., Köhl J. Monitoring and cell-specific deletion of C5aR1 using a novel floxed GFP-C5aR1 reporter knock-in mouse. 2015 J. Immunol. 194:1841-1855.

Current Funding

IRTG 1911. Project C7 The role of complement in transcriptional Th2 programming of pulmonary dendritic cells in allergic asthma