Background/Purpose: Cytokines produced during T_H17 response, IL-17A and IL17F drive inflammation and autoimmunity. They also act as a bridge between adaptive and innate immunity. Immune deposits are formed in vascular sites in autoimmunity and often demonstrate the excessive presence of immune complexes (ICs) and activated complement products. ICs drive nephropathic changes in SLE. Thus, we examined whether these immune reactants can activate naive CD4⁺ T-cells to generate T_H17 like cells. Furthermore to elucidate the mechanism by which ICs triggered the generation of T_H17 like population, we also examined the presence of low affinity Fc-receptors on activated naïve CD4⁺T-cells. 

Methods: Naïve CD4⁺CD45RA⁺ T-cells obtained from SLE patients were activated using plate bound ICs (10 mg/ml) and soluble C5b-9 (2.5 mg/ml) in the presence of anti-CD3 (0.25 mg/ml). Post activation cells were cultured in the presence of IL-1β (25 ng) IL-2 (10 ng), IL-6 (50 ng), IL-23 (25 ng), and TGF-β1 (10 ng) in each ml of RPMI. On day 9^th culture soups were analyzed for cytokines and flow analysis was performed for IL-17A, IL-17F, IL-21, and IL-22. qRT-PCR was performed for rorc and ifng  IFN pathway genes were analyzed using qRT-PCR IFN-arrays (Applied Biosystems). Activated cells were analyzed for binding to labeled ICs and expression of fcgr3a gene transcripts. 

Results and Conclusion: Our results demonstrate that ICs via FcγRIIIa ligation on activated naïve CD4⁺ T-cells generate T_H17 like population. We observed increased expression of rorc transcripts and statistically significant increase in IL-17A, IL-17F, IL-21, and IL-22 in the culture supernatant and an increase in cytokine producing population in flow analysis in response to ICs treatment. In addition IC mediated signal in CD4⁺ T-cells also generated an IFN-γ^high+ population. ICs and complement provided a co-stimulatory signal that was strong and divergent from the traditional CD28 co-stimulatory signal. CD4⁺ T-cells activated using anti-CD3+ICs+C5b-9 induced expression of fcgr3a transcripts and membrane FcγRIIIa protein. These activated cells showed statistically significant increase in binding to labeled ICs and AHG in flow analysis. These results for the first time demonstrate a possible role for FcγRIIIa in the generation of T_H17 like cells. Our IFN array analysis also showed increase in type 1 IFN genes. In autoimmune disease a co-operation between type 1 IFNs and T_H17 has been observed. Our data suggest that both of these responses are driven by ICs and complement in CD4⁺ T-cells. Generation of T_H17 like population and IFN-γ producing cells will contribute to the development of lupus nephritis, which could occur locally in the kidney. These findings are important in that the activating membrane co-stimulatory signal from CD28 and ICOS are counteracted by CTLA4 and PD1 inhibitory signal during immune contraction. An activating signal from ICs and complement in immune contraction can tip the balance in favor of activating signal that may lead to breakdown of peripheral tolreance. Thus the data present identifies a new pathway by which ICs and complement will drive the autoimmune pathology.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/fc%ce%b3riiia-ligation-in-human-peripheral-cd4-t-cells-generate-th17-like-population/