How Complement Stimulates B Cell Responses
A Virtual Mini-Symposium
Antigen binding to complement proteins is important for effective humoral immune responses. With renewed focus on antibody-based vaccine approaches, the potential of harnessing complement to elicit stronger and more durable responses could be of interest to the HIV vaccine research field. The Global HIV Vaccine Enterprise (the Enterprise) will host a web-based symposium presenting historical and recent data on the potential roles of the complement system in modulating humoral immunity. Presentations will be followed by a lively discussion on the relevance of these findings to current HIV vaccine research and their potential to advance the field in a new direction.
Guinea pigs defective in complement fail to trigger class-switching and B cell memory formation in response to antigens (1). Complement activation is important for efficient antigen trafficking to germinal centers, where complement-bound antigen is stored by follicular DCs for presentation to B cells (2,3). Myeloid DCs are also known to more effectively take up complement-bound HIV (4). In addition, complement binding to HIV affects intracellular processing patterns by DCs, which enhances MHC class I presentation (5).
There have been a few attempts to use the adjuvant-like properties of complement proteins to improve the immunogenicity of HIV vaccine candidates. For example, fusing gp120 to C3d, one of the components of the complement cascade, led to modestly enhanced immunogenicity of a DNA vaccine candidate (6-8). Complement binding also improved CTL responses to a Friend Leukemia Virus Env (9). It has been proposed that the poor immunogenicity of HIV Env is due to weak binding between gp120 and gp140 and complement proteins and, therefore, instead of being trafficked to germinal centers, the antigens are removed from the site of injection and cleared by the liver (10).
12:00-2:00 PM EST, 9 September 2014
Speakers and Panelists
- Michael Carroll, Harvard Medical School
- Galit Alter, Ragon Institute
- Michael Frank, Duke University
- Georgia Tomaras, Duke University
- Catarina Hioe, New York University
To view abstracts for these presentations, click here
- Böttger, E. C. et al. Impaired humoral immune response in complement C3-deficient guinea pigs: absence of secondary antibody response. Eur. J. Immunol. 16, 1231–1235 (1986).
- Carroll, M. C. The role of complement in B cell activation and tolerance. Adv. Immunol. 74, 61–88 (2000).
- Nielsen, C. H. & Leslie, R. G. Q. Complement’s participation in acquired immunity. J. Leukoc. Biol. 72, 249–261 (2002).
- Tjomsland, V. et al. Complement opsonization of HIV-1 enhances the uptake by dendritic cells and involves the endocytic lectin and integrin receptor families. PloS One 6, e23542 (2011).
- Tjomsland, V. et al. Complement opsonization of HIV-1 results in a different intracellular processing pattern and enhanced MHC class I presentation by dendritic cells. Eur. J. Immunol. 43, 1470–1483 (2013).
- Bower, J. F., Yang, X., Sodroski, J. & Ross, T. M. Elicitation of neutralizing antibodies with DNA vaccines expressing soluble stabilized human immunodeficiency virus type 1 envelope glycoprotein trimers conjugated to C3d. J. Virol. 78, 4710–4719 (2004).
- Green, T. D., Montefiori, D. C. & Ross, T. M. Enhancement of antibodies to the human immunodeficiency virus type 1 envelope by using the molecular adjuvant C3d. J. Virol. 77, 2046–2055 (2003).
- Liu, F. et al. Independent but not synergistic enhancement to the immunogenicity of DNA vaccine expressing HIV-1 gp120 glycoprotein by codon optimization and C3d fusion in a mouse model. Vaccine 22, 1764–1772 (2004).
- Bánki, Z. et al. Complement as an endogenous adjuvant for dendritic cell-mediated induction of retrovirus-specific CTLs. PLoS Pathog. 6, e1000891 (2010).
- Jiang, H., Hester, G., Liao, L., Montefiori, D. C. & Frank, M. M. Mechanisms by which HIV envelope minimizes immunogenicity. Immunol. Res. 49, 147–158 (2011).