Toll-like Receptor Agonists Alter the CD8+ T Cell Response Hierarchy in Neonates During Respiratory Syncytial Virus Infection
Methods: Intranasal RSV infection of CB6F1 adult hybrid mice generates a strongly dominant RSV-specific CD8+ T cell response to a Kd- restricted peptide (SYIGSINNI) from the M2 protein of RSV, and a numerically subdominant response to a RSV epitope from the M protein (NAITNAKII, DbM187-195). Neonatal mice, however, generate a more co-dominant response to these two epitopes as determined by flow cytometry. To define the role of antigen-presenting cell (APC) in driving the T cell response, Toll-like receptor (TLR) agonists that active APC were administered at the time of RSV infection.
Results: TLR agonist treatment of neonatal mice resulted in a more adult-like CD8+ T cell response hierarchy indicating a critical role for APC in driving T cell responses. Conventional dendritic cells (cDC) are important professional APC in the lung. Evaluation of cDC during RSV infection demonstrates age-dependent differences in the number of cDCs, with diminished costimulatory capacity in neonates. TLR agonist treatment at the time of RSV infection of neonates increased expression of costimulatory molecules, CD80 and CD86, on two subsets of cDC, the CD103+DC and CD11b+DC. Partial blockade of CD80 and CD86 during RSV infection of neonates treated with a TLR agonist reversed the T cell response hierarchy back to a co-dominant response, indicating the importance of cDC costimulatory molecule expression. Surprisingly, during RSV infection, both CD103+DC and CD11b+DC are able to effectively present antigen to CD8+ T cells to stimulate proliferation, in contrast to other infection models that characterized CD11b+DC as poor stimulators of CD8+T cells.
Conclusion: The unique age-dependent changes in immunity seen in RSV infection, and the ability to modify both CD103+DC and CD11b+DC to alter the character of RSV-specific CD8+ T cell responses can be used to develop vaccines that target the youngest and most vulnerable in the population.
K. Morabito, None
B. Graham, None