IL-6 Production by TLR-Activated APC Broadly Enhances Aged Cognate CD4 Helper and B Cell Antibody Responses In Vivo

Abstract

Naive CD4 T cell responses, especially their ability to help B cell responses, become compromised with aging. We find that using APC pre-treated ex vivo with TLR agonists, polyI:C and CpG, to prime naive CD4 T cells in vivo, restores their ability to expand and become germinal center T follicular helpers and enhances B cell IgG antibody production. Enhanced helper responses are dependent on IL-6 production by the activated APC. Aged naive CD4 T cells respond sub-optimally to IL-6 compared to the young, such that higher doses are required to induce comparable signaling. Pre-activating APC overcomes this deficiency. Responses of young CD4 T cells are also enhanced by pre-activating APC with similar effects but with only partial IL-6 dependency. Strikingly, introducing just the activated APC into aged mice significantly enhances otherwise compromised antibody production to inactivated influenza vaccine. These findings reveal a central role for production of IL-6 by APC during initial cognate interactions in the generation of effective CD4 T cell help, which becomes greater with age. Without APC activation aging CD4 T cell responses shift towards IL-6-independent Th1 and ThCTL responses. Thus, strategies that specifically activate and provide antigen to APC could potentially enhance Ab mediated protection in vaccine responses.

The properties of the unique age-associated B cell subset reveal a shift in strategy of immune response with age

“…Our recent studies indicate that the generation of aged CD4 help is more dependent on PRR stimulation, in that the APC that initiate the CD4 their response need to be highly activated. Since the CD4 helper response is more PRR dependent, GCB generation is indirectly more dependent on pathogen recognition [7]. Second ABC, as described here, become a major component of the primary B cell response and they are highly dependent on direct PRR stimulation.…”

“…GC-Tfh (CXCR5 hi , Bcl6 hi , GL-7 + CD4 + T cells by FACS) were enumerated in groups of mice harvested at 0, 3, 5, 7, 9, 11 and 13 days post infection. Potential helper CD4 T cells producing IL-21 were determined by intracellular cytokine staining [7] and are expressed as the % of total CD4 T cells.…”

“…Spleens of unimmunized young and aged B6 mice were analyzed by FACS as in our recent study [7] and CD19 + / B220 + cells were analyzed for expression of CD23 and CD21/35. FOB express high CD23 and CD21/35; MZB are CD23 − / CD21/35 + and ABC express neither.…”

“…In contrast, the FOB response decreases with age, and remains helper T cell dependent, while generation of T helper cells is reduced (Figure 2). Our recently published studies indicate the FOB response to inactivated influenza vaccine, can be markedly enhanced when the aged naive CD4 receive their cognate signals by TLR-agonist treated DC (*DC-APC) [7]. Thus both the ABC and FOB responses in the aged are much more dependent on pathogen-associated danger signals, which in the case of IAV.…”

“…We and others have shown there is a dramatic decrease in the number and function of naive CD4 T cells with age [3,4] that leads to a reduced generation of helper T cell effectors [2,5]. As a consequence, there is also a reduced generation of germinal center B cell (GCB) responses, and generation of fewer isotype-switched Ab-secreting plasma cells (PC), long-lived PC (LLPC) [2,5–7] as well as reduced generation of memory B cells all of which are critical for effective immunity. The generation of memory CD4 T cells from aged naive cells is also severely compromised [8,9].…”