During Viral Infection of the Respiratory Tract, CD27, 4-1BB, and OX40 Collectively Determine Formation of CD8+ Memory T Cells and Their Capacity for Secondary Expansion

Abstract

Independent studies have shown that CD27, 4-1BB, and OX40 can all promote survival of activated CD8+ T cells. We have therefore compared their impact on CD8+ memory T cell formation and responsiveness within one, physiologically relevant model system. Recombinant mice, selectively lacking input of one or two receptors, were challenged intranasally with influenza virus, and the immunodominant virus-specific CD8+ T cell response was quantified at priming and effector sites. Upon primary infection, CD27 and (to a lesser extent) 4-1BB made nonredundant contributions to accumulation of CD8+ virus-specific T cells in draining lymph nodes and lung, while OX40 had no effect. Interestingly though, in the memory response, accumulation of virus-specific CD8+ T cells in spleen and lung critically depended on all three receptor systems. This was explained by two observations: 1) CD27, 4-1BB, and OX40 were collectively responsible for generation of the same memory CD8+ T cell pool; 2) CD27, 4-1BB, and OX40 collectively determined the extent of secondary expansion, as shown by adoptive transfers with standardized numbers of memory cells. Surprisingly, wild-type CD8+ memory T cells expanded normally in primed OX40 ligand- or 4-1BB ligand-deficient mice. However, when wild-type memory cells were generated in OX40 ligand- or 4-1BB ligand-deficient mice, their secondary expansion was impaired. This provides the novel concept that stimulation of CD8+ T cells by OX40 and 4-1BB ligand during priming imprints into them the capacity for secondary expansion. Our data argue that ligand on dendritic cells and/or B cells may be critical for this.

Functional Dichotomy between OX40 and 4-1BB in Modulating Effector CD8 T Cell Responses

“…Initial data from OX40 Ϫ/Ϫ and OX40 ligand (OX40L) Ϫ/Ϫ mice suggested that OX40-OX40L is not required for CD8 priming to lymphocytic choriomeningitis virus (LCMV), vesicular stomatitis virus, and influenza virus (17,18). In contrast, CD8 contact hypersensitivity (18) and alloantigen responses (19) were suppressed, and secondary responses to influenza virus were also impaired (20), in OX40L Ϫ/Ϫ mice. Moreover, recent studies using OX40-deficient TCR-transgenic CD8 T cells showed that OX40 was required for cell survival during certain primary (21) and secondary CD8 T cell responses (22).…”

Death receptor 3 is essential for generating optimal protective CD41 T‐cell immunity against Salmonella

“…Thus, costimulation by various members of the TNFRSF augments the magnitude of the primary and/or secondary T-cell response and contributes to host protection against infection [3,4]. The involvement of different TNFRSF members in regulating T-cell responses varies however, with some TNFRSF members contributing preferentially towards enhanced memory generation [3] or local responses within the inflamed tissue [5]. The requirement for multiple TNFRSF members probably arises due to distinct temporal patterns of costimulatory receptor and ligand expression, which are likely to be controlled by factors such as pathogen type and virulence [4,6].…”

“…Collectively, these receptors provide costimulatory signals to antigen-stimulated T cells that enhance their expansion and survival. Thus, costimulation by various members of the TNFRSF augments the magnitude of the primary and/or secondary T-cell response and contributes to host protection against infection [3,4]. The involvement of different TNFRSF members in regulating T-cell responses varies however, with some TNFRSF members contributing preferentially towards enhanced memory generation [3] or local responses within the inflamed tissue [5].…”

Late Signals from CD27 Prevent Fas-Dependent Apoptosis of Primary CD8+ T Cells

“…This suggests that the CD27/CD27L interaction leads to the production of effector memory cells, which is important for the secondary immune response. CD8 ϩ T cells lacking CD27 costimulation, as well as 4-1BB and OX40, during the primary infection, have also been show to have a decreased capacity to expand to secondary infection (30).…”