Memory CD4+ T cells induce innate responses independently of pathogen

Abstract

Inflammation induced by recognition of pathogen-associated molecular patterns dramatically impacts subsequent adaptive responses. We asked if the adaptive immune system can also affect the character and magnitude of innate inflammatory responses. We find that the response of memory, but not naïve, CD4+ T cells enhances production of multiple innate inflammatory cytokines and chemokines (IIC) in the lung, and that during influenza infection, this leads to early control of virus. Memory CD4+ T cell induced IIC and viral control require cognate antigen recognition and are optimal when memory cells are either T helper type 1 (TH1)- or TH17-polarized, but are independent of interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) production and do not require activation of conserved pathogen recognition pathways. This represents a novel mechanism by which memory CD4+ T cells induce an early innate response that enhances immune protection against pathogens.

Memory CD4+T-cell–mediated protection depends on secondary effectors that are distinct from and superior to primary effectors

“…In agreement with studies using in vitro-generated memory cells (19), in vivo PR8 memory cells upregulated CD69 1-2 d earlier in the lung and draining lymph nodes (dLN) than did naive cells (Fig. 1A), indicating a more rapid activation of memory cells, but 4 d postinfection (dpi) the expansion of naive and memory donors was similar (Fig.…”

“…2D). This result stresses the necessity of late-acting events and also is consistent with some protective contribution from earlier-acting memory cell functions (19). These results suggest that 2°effectors are key contributors to memory CD4 + T-cell-mediated protection against IAV.…”

“…Memory CD4 + T cells regulate innate immunity during the initial days of IAV infection (19) and provide help for the enhanced antibody production that is evident by 7 dpi (20). We reasoned that these functions would occur by 5 dpi, but, as described above, we found that 2°effectors enter the lung only at 6 dpi and peak at 7-8 dpi (Fig.…”

“…In vivo PR8-primed memory cells were generated and reisolated as described (19) by transferring naive HNT cells to nude hosts that then were infected with PR8 and allowed to recover at least 30 d before reisolation of donor CD4 + T cells from SLO and lung. Similarly, polyclonal memory CD4 + T cells were isolated from SLO and lungs of mice that had been primed with PR8 at least 30 d previously.…”

Vaccination and heterologous immunity: educating the immune system

“…For instance, Swain and colleagues observed that transferring memory IAV-specific CD4 cells into naive mice could prime an IAV response without the need for TLR activation. 21 Data from research into heterologous immunity of adult mice and humans, as well as epidemiological data from vaccination studies of children, suggest that the sequence of infection or vaccination can lead to either detrimental or beneficial effects on subsequent unrelated infections. These data would be consistent with the idea that they play a role in the education of the immune system and that there may be a more optimum vaccination strategy, which would be beneficial to the maturation of the immune system.…”