The immune responses, including those modulated by Toll-like receptor (TLR) 4 set the stage for the adaptive allergic immune response. Our preliminary data have uncovered a potential novel immune pathway in the lung by linking TLR4 activation with upregulation of cytotoxic T lymphocyte antigen 4 (CTLA4). We demonstrate that CTLA4 signals can inhibit allergic responses in experimental asthma. Specifically, we show that blocking CTLA4 increases allergic inflammation, whereas over expression of CTLA4 suppresses allergic inflammation. Two pathways extend these findings. First, innate TLR4 ligands upregulate CTLA4 both in vitro and in vivo and inhibit experimental asthma; and consistent with this observation, TLR4 mutant mice, which have deficient TLR4 responses, have enhanced allergic responses. Second, increased CTLA4, by CD45RB signals, decreases allergic responses. Because all three molecules (CTLA4, TLR4, and CD45RB) are expressed on T regulatory (Tregs) cells, we will investigate the function of Tregs in the TLR4 and CD45RB mediated inhibition of experimental asthma. Interestingly, our preliminary data also show that the endotoxin component lipid A, which is a TLR4 ligand, ameliorates experimental asthma. Consistent with our murine results, epidemiological studies show that exposure to an endotoxin rich environment decreases the risk of childhood asthma. Furthermore, in our model, the depletion of Treg cells in vivo enhances allergic responses and blocks TLR4 ligand mediated inhibition of experimental asthma. These observations indicate that TLR4 mediated suppression of asthma is mediated by CTLA4 expressing Tregs. Thus, our hypothesis is that TLR4 attenuates the adaptive immune response by modulating upregulation of CTLA4, a critical pathway in the suppression of allergic inflammation.
Aim 1 will characterize the role of CTLA4 in the suppression of allergic inflammation by determining how inhibition of CTLA4 (using anti-CTLA4 antibody or deficient mice) promotes allergic inflammation, and how increased CTLA4 expression decreases allergic inflammation (using CTLA4 transgenics that overexpress CTLA4, or CD45RB antibody).
Aim 2 will investigate whether TLR4 signals modulate CTLA4 expression in vivo.
Aim 3 will determine the mechanisms by which TLR4 signals suppress allergic inflammation, including the cellular components (APC, T cells), and whether CTLA4 signals enhance TLR4-induced suppressor activity in allergic inflammation.
Aim 4 will determine the molecular mechanisms by which TLR4 and CD45RB regulate CTLA4 expression in T cells by analysis of the CTLA4 promoter region. The objective of this project is to identify novel pathways, and potential therapeutic targets by which innate immunity modulates allergic asthma.
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