FIG 8.

Proposed mechanism for reduction of CHIKV-induced pathology by IL-2 Ab Cx. Upon CHIKV infection in the joint footpad, resident sentinels such as macrophages and DCs sense the virus. Virus stimulation induces activation of macrophages, which secrete proinflammatory cytokines and chemokines to attract other immune cell populations. Meanwhile, DCs phagocytose viral particles and differentiate into mature migratory DCs to upregulate MHCII and costimulatory molecules. The matured DCs migrate to the draining pLN and present viral antigen to naive T cells. Upon interaction with their cognate antigen, naive T cells are activated into Teff cells and enter the cell cycle to expand clonally. These expanded CHIKV-specific Teff cells migrate toward the site of infection in response to secreted T cell chemokines. The presence of CHIKV-specific Teff cells exacerbates the proinflammatory milieu and gives rise to the inflamed joint pathology observed. In the event of IL-2 Ab Cx pretreatment, expanded Tregs will be present in large number in all the secondary lymphoid organs. As the mature DCs carrying CHIKV antigen arrive at the draining LN, Tregs compete with naive T cells to interact with these DCs. Treg-DC interaction then causes mature DCs to downregulate their costimulatory molecules and results in the DCs presenting CHIKV antigens to naive T cells in the absence of costimulatory signals. Activation of T cells without costimulation is likely to drive the T cells into G₁ arrest, resulting in anergy. Anergic T cells are not able to migrate to the site of infection in response to chemoattractants. Abrogation of CHIKV-specific Teff cells infiltration in the site of infection prevents exacerbation of proinflammatory environment, thus preventing the inflamed-joint pathology.