ICOS signaling promotes a secondary humoral response after re-challenge with Plasmodium chabaudi chabaudi AS

Abstract

The co-stimulatory molecule ICOS is associated with the induction and regulation of T helper cell responses, including the differentiation of follicular helper T (Tfh) cells and the formation and maintenance of memory T cells. However, the role of ICOS signaling in secondary immune responses is largely unexplored. Here we show that memory T cell formation and maintenance are influenced by persistent infection with P. chabaudi chabaudi AS infection, as memory T cell numbers decline in wild-type and Icos-/mice after drug-clearance. Following drug-clearance Icos-/mice display a relapsing parasitemia that occurs more frequently and with higher peaks compared to wild-type mice after re-challenge. The secondary immune response in Icos-/mice is characterized by significant impairment in the expansion of effector cells with a Tfh-like phenotype, which is associated with a diminished and delayed parasite-specific Ab response and the absence of germinal centers. Similarly, the administration of an anti-ICOSL antagonizing antibody to wild-type mice before and after reinfection with P. c. chabaudi AS leads to an early defect in Tfh cell expansion and parasite-specific antibody production, confirming a need for ICOS-ICOSL interactions to promote memory B cell responses. Furthermore, adoptive transfer of central memory T (T CM) cells from wild-type and Icos-/mice into tcrb-/mice to directly evaluate the ability of T CM cells to give rise to Tfh cells revealed that T CM cells from wild-type mice acquire a mixed Th1-and Tfh-like phenotype after P. c. chabaudi AS infection. While T CM cells from Icos-/mice expand and display markers of activation to a similar degree as their WT counterparts, they displayed a reduced capacity to upregulate markers indicative of a Tfh cell phenotype, resulting in a diminished humoral response. Together these findings verify that ICOS signaling in memory T cells plays an integral role in promoting T cell effector responses during secondary infection with P. c. chabaudi AS.

ICOS expression is required for maintenance but not the formation of germinal centers in the spleen in response to P. yoelii infection

“…However, these structures were observed in WT mice, indicating that ICOS signaling is necessary to promote GC formation during secondary infection. This observation is in accordance with what was previously reported in other models [4,19].…”

“…However, like what we observed in the P. chabaudi model after secondary infection [19] the secondary humoral response was impaired without ICOS. Although, no parasites were ever detectable in the blood smears, indicating that the presence of Ag-specific Abs, though of a lower affinity, was sufficient to protect these mice.…”

IgM+and IgM-memory B cells represent heterogeneous populations capable of producing class-switched antibodies and germinal center B cells upon re-challenge withP. yoelii

“…P. chabaudi establishes a persistent infection after rechallenge, just as it did after primary infection but at a lower level of parasitemia. 58 Thus, the Abs generated in response to primary infection with P. yoelii are more effective at preventing re-establishment of infection than those produced in response to P. chabaudi infection. Consequently, we speculate that critical epitopes recognized by the BCR of IgM + MBCs and naïve B cells are preferentially bound by affinity-matured circulating Ag-specific Abs or high-affinity BCRs associated with swIg + MBCs after re-infection with P. yoelii.…”

Memory Generation and Re-Activation in Food Allergy

“…ICOS-ICOSL interactions are important because ICOS-deficient mice exhibit defective IL-4 production and impaired IgE responses following KLH-alum immunization. 107 Also, in secondary responses, expansion of antigen-specific B cells and class-switched antibody responses are compromised in the absence of ICOS signaling. 73 , 108 The fact that ICOS is essential for the maintenance of the memory Tfh cell phenotype 108 may explain the impaired secondary responses observed with ICOSL blockade.…”