Abstract
The T cell coinhibitory receptor CTLA-4 has been implicated in the down-regulation of T cell function that is a quintessential feature of chronic human filarial infections. In a laboratory model of filariasis, Litomosoides sigmodontis infection of susceptible BALB/c mice, we have previously shown that susceptibility is linked both to a CD4+ CD25+ regulatory T (Treg) cell response, and to the development of hyporesponsive CD4+ T cells at the infection site, the pleural cavity. We now provide evidence that L. sigmodontis infection drives the proliferation and activation of CD4+ Foxp3+ Treg cells in vivo, demonstrated by increased uptake of BrdU and increased expression of CTLA-4, Foxp3, GITR, and CD25 compared with naive controls. The greatest increases in CTLA-4 expression were, however, seen in the CD4+ Foxp3- effector T cell population which contained 78% of all CD4+ CTLA-4+ cells in the pleural cavity. Depletion of CD25+ cells from the pleural CD4+ T cell population did not increase their Ag-specific proliferative response in vitro, suggesting that their hyporesponsive phenotype is not directly mediated by CD4+ CD25+ Treg cells. Once infection had established, killing of adult parasites could be enhanced by neutralization of CTLA-4 in vivo, but only if performed in combination with the depletion of CD25+ Treg cells. This work suggests that during filarial infection CTLA-4 coinhibition and CD4+ CD25+ Treg cells form complementary components of immune regulation that inhibit protective immunity in vivo.
Original language | English |
---|---|
Pages (from-to) | 4626-34 |
Number of pages | 9 |
Journal | The Journal of Immunology |
Volume | 179 |
Issue number | 7 |
Publication status | Published - 2007 |
Keywords / Materials (for Non-textual outputs)
- Animals
- Antibody Formation
- Antigens, CD
- Antigens, Differentiation
- CD4-Positive T-Lymphocytes
- Cell Survival
- Cells, Cultured
- Female
- Filariasis
- Filarioidea
- Forkhead Transcription Factors
- Interleukin-2 Receptor alpha Subunit
- Mice
- Mice, Inbred BALB C