CD4 and CD8 T Cell Memory Interactions Alter Innate Immunity and Organ Injury in the CLP Sepsis Model

Abstract

The role of T cell memory in sepsis is poorly understood. Recent work has demonstrated that mice exposed to frequent antigenic stimulation, in contrast to laboratory mice, better recapitulate the human T cell repertoire. This difference may profoundly alter responses to inflammatory insults. We induced isolated T cell memory by inoculating C57Bl/6 mice with an anti-CD3ϵ activating antibody, a process we term “immune education.” These mice were subjected to the cecal ligation and puncture (CLP) model of sepsis and responses were compared to those of isotype-treated controls. CLP-induced increases in 1) CD4 T cell production and serum levels of IFNγ, 2) CD8 T cell granzyme B levels, and 3) innate cell function were all more pronounced in educated mice than in control mice. Immune education increased CLP-induced liver injury and decreased survival. The differences in responses to CLP were not recapitulated in mice with either isolated CD4 or isolated CD8 T cell memory. Relative to controls, CLP in educated CD8−/− mice (isolated CD4 memory) increased monocyte-derived dendritic cells. Combined CD4 and CD8 memory did not increase monocyte-derived dendritic cells; this combination recapitulated increases in neutrophil and inflammatory monocyte numbers in educated wild-type mice. Induction of T cell memory prior to CLP alters immune responses, organ function, and survival. Both CD4 and CD8 memory T cells play important and independent roles in this response. These findings have profound implications for the development of murine models of human inflammatory disorders such as infection and sepsis.

Angiotensin II enhances bacterial clearance via myeloid signaling in a murine sepsis model

“…In bovine bacteremia, angiotensin-II–treated animals displayed lower levels of both IL-6 and IL-10 versus vehicle-treated controls ( 27 ). In our study, mice that received angiotensin-II alone displayed no elevations in IFN-γ, a cytokine that we and others have shown to be an important mediator of tissue autoinjury in the acute response to systemic inflammatory stimulus ( 28 )( 29 ). One interpretation of the serum cytokine levels is that angiotensin-II alters the kinetics of the inflammatory response to CLP, initially augmenting and subsequently limiting systemic inflammation, promoting initial bacterial defense, and limiting subsequent collateral organ dysfunction.…”

T cell activation and IFNγ modulate organ dysfunction in LPS-mediated inflammation

“…showed that induced adaptive immune memory altered the magnitude of organ dysfunction following CLP. 1,34 The experiments described here identify one potential mechanism. These studies indicate that the combination of TCR-and TLR4-mediated effects on T cell and DC interactions altered the response to LPS-induced inflammation and cellular dysfunction.…”

“…Therefore, murine models of inflammatory disease may not appropriately reflect the role played by adaptive immunity 3,4 . Our recent work showed that induced adaptive immune memory altered the magnitude of organ dysfunction following CLP 1,34 . The experiments described here identify one potential mechanism.…”

“…Recent literature indicates that the adaptive immune system may play a more proximal role in modulating initial responses to pathogenic challenge than previously appreciated 1,2 . However, studying the contribution of the adaptive immune system to the initiation of the inflammatory response has been limited in part by lack of a well‐developed memory T cell compartment in laboratory mice 3,4 .…”

“…Recent literature indicates that the adaptive immune system may play a more proximal role in modulating initial responses to pathogenic challenge than previously appreciated. 1,2 However, studying the contribution of the adaptive immune system to the initiation of the inflammatory response has been limited in part by lack of a well-developed memory T cell compartment in laboratory mice. 3,4 Our recent work in murine cecal ligation and puncture (CLP) demonstrated that induction of a robust memory T cell compartment prior to challenge influenced List of abbreviations: APCs, Antigen presenting cells; BUN, Blood urea nitrogen; CD3, anti-CD3eta; CD3LPSLo, CD3 + Low dose LPS; cDCs, Classical dendritic cells; CLP, Cecal Ligation and Puncture; Iso, Isotype; LPS, Lipopolysaccharide; LPSHi, High dose LPS; LPSLo, Low dose LPS; MFI, Median fluorescence intensity; MHC, Major histocompatibility complex; MoDCs, Monocyte-derived dendritic cells; TCR, T cell Receptor; TLR, Toll-like receptor innate immune responses and increased organ dysfunction.…”