Influenza infection results in local expansion of memory CD8+ T cells with antigen non-specific phenotype and function

Abstract

Summary Primary viral infections induce activation of CD8+ T cells responsible for effective resistance. We sought to characterize the nature of the CD8 + T cell expansion observed after primary viral infection with influenza. Infection of naive mice with different strains of influenza resulted in the rapid expansion of memory CD8 + T cells exhibiting a unique bystander phenotype with significant up-regulation of natural killer group 2D (NKG2D), but not CD25, on the CD44 high CD8+ T cells, suggesting an antigen non-specific phenotype. We further confirmed the non-specificity of this phenotype on ovalbuminspecific (OT-I) CD8 + T cells, which are not specific to influenza. These nonspecific CD8 + T cells also displayed increased lytic capabilities and were observed primarily in the lung. Thus, influenza infection was shown to induce a rapid, antigen non-specific memory T cell expansion which is restricted to the specific site of inflammation. In contrast, CD8 + T cells of a similar phenotype could be observed in other organs following administration of systemic agonistic anti-CD40 and interleukin-2 immunotherapy, demonstrating that bystander expansion in multiple sites is possible depending on whether the nature of activation is either acute or systemic. Finally, intranasal blockade of NKG2D resulted in a significant increase in viral replication early during the course of infection, suggesting that NKG2D is a critical mediator of anti-influenza responses prior to the initiation of adaptive immunity. These results characterize further the local bystander expansion of tissue-resident, memory CD8 + T cells which, due to their early induction, may play an important NKG2D-mediated, antigen non-specific role during the early stages of viral infection.

Out-of-Sequence Signal 3 Paralyzes Primary CD4+ T-Cell-Dependent Immunity

“…We and others have previously shown that these “bystander” activated CD8 + T cells perform their function in a more “NK-like” fashion using alternative receptors such as NKG2D for targeting transformed and virally infected cells rather than TCR mediated recognition (Chu et al, 2013; Sckisel et al, 2014; Tietze et al, 2011). Thus, the induction of bystander memory T activation, which is driven by cytokines and not antigen, necessitates the emergence of another control pathway which suppresses naïve CD4 + T cell expansion even with TCR triggering resulting in paralysis of primary T cell responses.…”

Aging influences the response of T cells to stimulation by the ellagitannin, oenothein B

“…This suggests that they may be prime targets for immunomodulatory food products. While typically associated with adaptive immunity, memory T cells can also play an important role in innate immunity through antigen-independent, bystander effects [19, 20, 33, 34]. Therefore, they may be another innate-like lymphocyte population, in addition to γδ T cells and NK cells, whose numbers and activity could be influenced by polyphenols.…”

Late administration of murine CTLA-4 blockade prolongs CD8-mediated anti-tumor effects following stimulatory cancer immunotherapy

“…for 5 days, respectively) and recombinant human interleukin-2 (5 × 10^5 IU i.p. twice a week for 2 weeks) as previously described [18]. The anti-mouse CD40 antibody (clone FGK115B3) was generated via ascites production in our laboratory, as previously described [18].…”

“…twice a week for 2 weeks) as previously described [18]. The anti-mouse CD40 antibody (clone FGK115B3) was generated via ascites production in our laboratory, as previously described [18]. Recombinant human IL-2 (IL-2; TECIN Teceleukin) was provided by the National Cancer Institute repository (Frederick, MD).…”

“…The OT-I adoptive transfer experiments were performed as previously described [18]. Briefly, prior to transfer OT-I Tg mice were vaccinated with ovalbumin/incomplete Freund’s emulsion to expand the memory T cell population.…”