Anil K. Chauhan, Ph.D.
Division of Adult and Pediatric Rheumatology
Role for complement system in disease pathology is well established. Complement deficiencies predispose individuals to the development of autoimmunity. Autoimmune patients show elevated levels of immune complexes (ICs), formed by the autoantibodies to self-antigens. Break down in peripheral tolerance and CD4+ effector T cells i.e. TH1, TH17, Treg play a crucial role in the development of autoimmunity. Autoimmune patients also show elevated hyperactive CD4+ helper cells. Complement opsonized ICs are known to be pathogenic. These events have been studied individually. However the function for complement proteins and ICs is considered to be limited to elimination of pathogens via killing or of stimulation of pahgocytois. Opsonized ICs uptake by antigen presenting cells (APC) via complement receptors (CRs) enhances the adaptive immune response. In recent years the immunoregulatory role for complement is emerging in modulating adaptive immunity and bridging the innate immunity to adaptive responses. Several groups implicate complement protein C5a in such responses (1). We have established a similar role for sublytic C5b-9, a late protein complex of complement pathway.
The roles of protein complexes such as ICs and non-lytic C5b-9 in T cell responses have not been investigated. Many of the recent reviews in fact suggest the lack of Fc receptors on CD4+ T cells surface, thus suggesting the inability of ICs to interact with CD4+ T cells (2-4). We observed that activated CD4+ cells indeed express FcgRIIIa, which upon ligation by ICs secret IFN-g. This event is non-T-bet mediated thus different from classical TH1 response. We recently have also observed that CD4+ T cells treated with ICs and C5b-9 gets activated and under appropriate cytokine polarizing condition also differentiate into effector T cell population. This is the first non-membrane costimulation of T cells and is important since it only appears during disease pathology.
My first focus is to understand the role of CD4+FcyRIIIa+IFN-y+ population in autoimmunity and in infectious disease. Traditional TH1, IFN-g is produced by TH1 genes such as STAT1 and others regulated by T-bet (5). I believe that IFN-g produced from IC activation involves PLC-g2 and is mediated via up regulation of genes such as DAP-12, which are not yet known to participate in IFN-y production in CD4+ T cells. The results from my laboratory suggest that in autoimmunity in fact T cells acquire signaling that is typically observed during B cell activation such as FcR-g-Syk-PLC-g2. We are investigating these events and attempting to correlate them with autoimmune pathology. These events will also be extremely important to understand the role of infectious diseases in the development of autoimmunity. We are using PCR arrays and RNAseq to further differentiate the canonical TH1 response to FcyRIIIa mediated IFN-y production.
The second project of interest to me is the co-stimulatory signal generated by C5b9 and ICs s in the generation of T effector population. Both TH1 and TH17 subsets cause disease pathology (6). We have already established the role of ICs and complement in substituting CD28 for the generation of IL-17A+, IL-22+ and iTreg cells. We also established their role in the generation of Tfh population. This signal also induced expression of Bcl6+, PD1+, CXCR5+, IL-21, and ICOS on naïve CD4+, known markers of Tfh (7-9). The production of IL-21 was three fold higher than that of a traditional signal. In addition, lymph nodes from a disease mouse showed cyto-conjugates of CD4+CD19+ cells with high expression of ICOS and PD1 and over ninety percent of these cells bound to ICs. These results prompted us to further explore the role for ICs in the formation of cyto-conjugates between T and B cells and their role in the development of ectopic germinal centers. These findings will establish a direct role of ICs and complement system in the generation of autoantibodies. ICs are known to be over thousand fold more immunogenic than the antigen alone. These studies will be done directly using cells obtained from the human blood and mouse models, including some of the knockout mice for genes such as Tbx21, a gene that encodes TH1 transcription factor. All these studies are translational work with a potential to develop a blocking agent specific for preventing undesired CD4+ differentiation into TH17 or alternately to develop a protocol for the generation of Treg cells from ICs and complement activation, a valuable approach for T-reg cell targeted therapies.
1. Hawlisch H & Kohl J (2006) Complement and Toll-like receptors: key regulators of adaptive immune responses. Molecular immunology 43(1-2):13-21.
2. Smith KG & Clatworthy MR (2010) FcgammaRIIB in autoimmunity and infection: evolutionary and therapeutic implications. Nature reviews. Immunology 10(5):328-343.
3. Nimmerjahn F & Ravetch JV (2008) Fcgamma receptors as regulators of immune responses. Nature reviews. Immunology 8(1):34-47.
4. Hogarth PM & Pietersz GA (2012) Fc receptor-targeted therapies for the treatment of inflammation, cancer and beyond. Nature reviews. Drug discovery 11(4):311-331.
5. Lazarevic V & Glimcher LH (2011) T-bet in disease. Nat Immunol 12(7):597-606.
6. Steinman L (2010) Mixed results with modulation of TH-17 cells in human autoimmune diseases. Nat Immunol 11(1):41-44.
7. Crotty S (2011) Follicular helper CD4 T cells (TFH). Annual review of immunology 29:621-663.
8. Morita R, et al. (2011) Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity 34(1):108-121.
9. Nurieva RI, et al. (2008) Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity 29(1):138-149.