Differential and temporal immunomodulation of α4 integrin receptors on memory T cells by Bordetella pertussis and Bordetella parapertussis infection in mice (173.24)

Abstract

Abstract The hallmarks of B. pertussis (Bp) infection are extreme lymphocytosis and delayed recovery, which are linked to pertussis toxin (PTX). We hypothesize that PTX interferes with imprinting of α4 integrins on T-cells leading to their compromised homing to respiratory mucosa. In a murine model, immunofluorescence of lung sections implies a delayed recruitment of leukocytes in Bp but not in B. parapertussis (Bpp) and B. pertussis PTX mutant (BpTOX6) on day 5 p.i; lymphocyte recruitment is restored at day 25 p.i in Bp. At day 5 p.i, in Bpp and BpTOX6 models we reveal by flow cytometry an increase of blood memory CD4+ cells (CD44high and CD45RBlow) that express α4β1, α4β7; the respective cells are reduced in Bp infection. However, their frequency is increased at day 25 p.i, confirming delayed immune response. In vitro assays reflect a PTX-mediated inhibition of blood lymphocytes α4 integrins dependent adhesion and migration toward VCAM-1. In Bp, a high percent of lung dendritic cells (DC) expressing MHC-II and CD86 persists through day 25 p.i; however, the percent of CCR7+ DC in Bp is lower than that in Bpp at day 5 p.i. Lastly, after co-culturing with isolated Bp-lung DC from day 5 p.i for 4 days, a reduced percent of allogeneic CD4+ cells expresses α4β1, α4β7 compared to the respective models with Bpp or BpTOX6. We conclude that α4 integrins play an important role in memory CD4+ cell migration in Bordetellae, and that PTX interferes with their imprinting early in Bp infection.