IFN-Induced Attrition of CD8 T Cells in the Presence or Absence of Cognate Antigen during the Early Stages of Viral Infections

Abstract

Profound lymphopenia has been observed during many acute viral infections, and our laboratory has previously documented a type I IFN-dependent loss of CD8 T cells immediately preceding the development of the antiviral T cell response. Most memory (CD44high) and some naive (CD44low) CD8 T cells are susceptible to IFN-induced attrition, and we show in this study that the IFN-induced attrition of CD8+CD44high T cells is associated with elevated activation of caspase-3 and caspase-8. We questioned whether TCR engagement by Ag would render CD8 T cells resistant to attrition. We tested whether a high concentration of Ag (GP33 peptide) would protect lymphocytic choriomeningitis (LCMV)-specific naive CD8 T cells (TCR transgenic P14 cells specific for the GP33 epitope of LCMV) and memory CD8 T cells (GP33-specific LCMV-immune cells) from depletion. Both naive P14 and memory GP33-specific donor CD8 T cells decreased substantially 16 h after inoculation with the Toll receptor agonist and IFN inducer, poly(I:C), regardless of whether a high concentration of GP33 peptide was administered to host mice beforehand. Moreover, donor naive P14 and LCMV-specific memory cells were depleted from day 2 LCMV-infected hosts by 16 h posttransfer. These results indicate that Ag engagement does not protect CD8 T cells from the IFN-induced T cell attrition associated with viral infections. In addition, computer models indicated that early depletion of memory T cells may allow for the generation for a more diverse T cell response to infection by reducing the immunodomination caused by cross-reactive T cells.

Concomitant type I IFN receptor‐triggering of T cells and of DC is required to promote maximal modified vaccinia virus Ankara‐induced T‐cell expansion

“…This phenomenon was less pronounced upon infection with VACV gp33 [12]. Interestingly, instead of enhancing T-cell function, IFN can also lead to T-cell attrition or activation induced cell death [13,14].…”

“…This phenomenon was less pronounced upon infection with VACV gp33 [12]. Interestingly, instead of enhancing T-cell function, IFN can also lead to T-cell attrition or activation induced cell death [13,14].To further study the impact of virus-induced IFN on the stimulation of virus-specific T-cell responses, we analyzed expansion of antigen-specific T cells upon infection with two closely related viruses, vaccinia virus (VACV) and modified vaccinia virus Ankara (MVA), which upon infection either suppress or induce IFN responses, respectively. VACV deploys a multitude of different strategies to evade immune surveillance.…”

Vaccination and heterologous immunity: educating the immune system

“…[60][61][62] Most of the in vivo data support the active attrition model. 61,63,64 Many viral infections in mouse and human induce a substantial loss in lymphocyte and leukocyte numbers in the early stages of infections. 65 A substantial loss in CD8 and CD4 T cell number during the first 5 days of LCMV infection parallels the levels of type 1 IFN production, does not occur in type 1 IFN receptor ko mice, 66 is blocked by antibody to type 1 IFN 67 and is mimicked by IFN-inducing toll receptor agonists, such as poly I:C. 66 The apoptotic loss of memory occurs prior to cell division.…”

“…65 A substantial loss in CD8 and CD4 T cell number during the first 5 days of LCMV infection parallels the levels of type 1 IFN production, does not occur in type 1 IFN receptor ko mice, 66 is blocked by antibody to type 1 IFN 67 and is mimicked by IFN-inducing toll receptor agonists, such as poly I:C. 66 The apoptotic loss of memory occurs prior to cell division. 63,66,68 An in silico virtual immune system model, IMMSIM, which unlike a biological system can selectively turn off either active or passive attrition, predicted that without the active attrition and apoptosis of memory T cells early in infection, crossreactive T cells might overwhelmingly dominate the response to an infection. 61,63 By selectively reducing the frequency of memory cells at the beginning of an immune response, there actually may develop a more diverse T cell response to a new pathogen, and that diversity may be beneficial to the host for control of the pathogen.…”

“…63,66,68 An in silico virtual immune system model, IMMSIM, which unlike a biological system can selectively turn off either active or passive attrition, predicted that without the active attrition and apoptosis of memory T cells early in infection, crossreactive T cells might overwhelmingly dominate the response to an infection. 61,63 By selectively reducing the frequency of memory cells at the beginning of an immune response, there actually may develop a more diverse T cell response to a new pathogen, and that diversity may be beneficial to the host for control of the pathogen. This prediction was further validated in vivo in elderly mice as they undergo less IFN-driven T cell attrition than do young mice.…”