CD8+ Memory T Cells Appear Exhausted within Hours of Acute Virus Infection

Abstract

CD8+ memory T cells are abundant, and are activated in a near-synchronous manner by infection, thereby providing a unique opportunity to evaluate the coordinate functional and phenotypic changes that occur in vivo within hours of viral challenge. Using two disparate virus challenges of mice, we show that splenic CD8+ memory T cells rapidly produced IFNγ in vivo, but, within 18–24 hours, IFNγ synthesis was terminated, and remained undetectable for ≥48 hours. A similar on/off response was observed in CD8+ memory T cells in the peritoneal cavity. Cessation of IFNγ production in vivo occurred despite the continued presence of immunostimulatory viral antigen, indicating that the initial IFNγ response had been actively down-regulated and that the cells had been rendered refractory to subsequent in vivo antigen contact. Down-regulation of IFNγ synthesis was accompanied by the upregulation of inhibitory receptor expression on the T cells, and ex vivo analyses using synthetic peptides revealed a concurrent hierarchical loss of cytokine responsiveness (IL-2, then TNF, then IFNγ) taking place during the first 24 hours following antigen contact. Thus, within hours of virus challenge, CD8+ memory T cells display the standard hallmarks of T cell exhaustion, a phenotype that has previously been associated only with chronic diseases, and that is generally viewed as a gradually-developing and pathological change in T cell function. Our data suggest that, instead, the “exhaustion” phenotype is a rapid and normal physiological T cell response.

Antigen-Specific Naive CD8+ T Cells Produce a Single Pulse of IFN-γ In Vivo within Hours of Infection, but without Antiviral Effect

“…An added benefit of this approach is that the cells are still synchronous at the time of analysis; such synchronicity is lost as individual cells, and their progeny, undergo cycles of cell division. Second, we wished to determine if naïve CD8 + T cells could exert rapid antiviral protective effects in vivo , and to compare this to the virus control imposed by CD8 + memory T cells, which suppress viral replication within ~6 hours (3). To do so, it was necessary to generate mice in which the abundance of naïve cells was approximately equivalent to the natural abundance of epitope-specific memory CD8 + T cells in LCMV-immune mice (1–2×10 5 cells/spleen).…”

“…As previously described (3, 11, 16, 17) 250 μg of Brefeldin A (Sigma, St. Louis MO) was injected i.v. into LCMV- or sham-infected mice at the indicated time points.…”

“…As previously described (3, 18) small (~5mg) pieces of spleen were harvested and stored in RNA later (Qiagen). RNA was isolated using RNeasy mini (Qiagen) with on-column DNA digestion according to manufacturer instructions.…”

“…In contrast, we have recently shown that LCMV replication within LCMV-immune mice is suppressed as soon as 6 hours post infection (p.i.) (3). This extraordinarily rapid protection conferred by virus-specific CD8 + memory T cells has been attributed to a combination of several factors.…”

Dynamic Tuning of Lymphocytes: Physiological Basis, Mechanisms, and Function

“…In the case of chronic infection, some alterations associated with tuning may later become epigenetically imprinted, and thereby less reversible, or lead to secondary alterations in a process that may be called adaptive differentiation (1,5). This interpretation has been recently proposed in connection to the phenomenon of T cell exhaustion (18,19).…”