Opposing effects of CD70 costimulation during acute and chronic lymphocytic choriomeningitis virus infection of mice

Abstract

T cell costimulation is important for T cell activation. The CD27/CD70 pathway contributes to effector and memory T cell development and is involved in T cell and B cell activation. CD27/CD70 is known for having opposing roles during different models of antigenic challenges. During primary T cell responses to influenza virus infection or during tumor challenges, CD27/CD70 costimulation has a positive role on T cell responses. However, during some chronic infections, constitutive triggering of this signaling pathway has a negative role on T cell responses. It is currently unclear what specific characteristic of an antigen determines the outcome of CD27/CD70 costimulation. We investigated the effect of a transient CD70 blockade during an acute or a chronic lymphocytic choriomeningitis virus (LCMV) infection in mice. Blockade of this pathway during acute LCMV infection (Armstrong strain) resulted in delayed T cell responses and decreased CD127 (interleukin-7 receptor α [IL-7Rα] chain) conversion. Upregulation of CD127 is an important event in T cell differentiation that heralds the passage of an effector T cell to a long-lived memory T cell. In contrast to the reduced CD8 T cell responses after CD70 blockade during acute infection, CD70 blockade during chronic LCMV infection resulted in increased CD8 T cell responses. Our data show the dual roles of this costimulatory pathway in acute versus persistent antigen challenge. Our findings suggest that antigen persistence may determine the effect of CD27/CD70 signaling on CD8 T cell responses. Tailored triggering or blockade of this costimulatory pathway may be important in vaccination regimens against acute or chronic pathogens.

Fig. 1.

Role of CD27/CD70 signaling during acute viral infection. (A) Experimental outline. Six- to 8-week-old C57BL/6J mice were treated with anti-CD70 at the indicated time points and infected with LCMV Armstrong. Mice were sacrificed at days 7 and 15 for analysis of cellular responses. (B) Intracellular cytokine staining after stimulation with several LCMV peptides at day 7 postinfection (fluorescence-activated cell sorting data from one representative experiment). Unstim, unstimulated cells. (C) Absolute numbers of IFN-γ-expressing CD8 T cells after LCMV peptide stimulation at day 7 postinfection. (D) Intracellular cytokine staining after stimulation with several LCMV peptides at day 15 postinfection (data from one representative experiment). (E) Absolute numbers of IFN-γ-expressing CD8 T cells after LCMV peptide stimulation at day 15 postinfection. (F) Memory conversion by CD70 blockade during acute viral infection (expression of CD127 on H-2D^b GP33-41-specific CD8 T cells from spleen at day 15 postinfection). MFI, mean fluorescence intensity. Data are from spleens in three separate experiments (each, n = 6). *, P < 0.05. α, anti.

Fig. 2.

Dual IFN-γ and TNF-α coexpression after CD70 blockade during acute viral infection. Data are from spleens in three separate experiments (each, n = 6). *, P < 0.5.

Fig. 3.

Virus-specific antibody responses after CD70 blockade during acute viral infection. ELISA was performed for detection of LCMV-specific IgG titers from serum at day 15 postinfection. Sera from an Armstrong-infected mouse at day 40 postinfection (memory) and from a naïve mouse were included as positive and negative controls, respectively. Data are from one representative experiment.

Fig. 4.

Role of CD27/CD70 signaling during chronic viral infection. (A) Experimental outline. Six- to 8-week-old C57BL/6J mice were treated with anti-CD70 at the indicated time points and infected with LCMV Cl-13. Mice were sacrificed at days 7 and 21 for analysis of cellular responses. (B) Intracellular cytokine staining after stimulation with several LCMV peptides at day 7 postinfection (data from one representative experiment). (C) Absolute numbers of IFN-γ-expressing CD8 T cells after LCMV peptide stimulation at day 7 postinfection. (D) Intracellular cytokine staining after stimulation with several LCMV peptides at day 21 postinfection (fluorescence-activated cell sorting data from one representative experiment). (E) Absolute numbers of antigen-specific CD8 T cells at day 21 postinfection. Data are from spleens in two separate experiments (each, n = 6).

Fig. 5.

No change in the phenotype of virus-specific CD8 T cells after CD70 blockade during chronic viral infection. First column shows percentage of CD8⁺ T cells that are H-2D^b GP33-41 tetramer positive. Second and third columns are gated on tetramer-positive cells and show expression of the memory marker CD127 and the inhibitory receptor PD-1. Data are from spleens in two separate experiments (each, n = 6).

Fig. 6.

Virus-specific antibody responses and viral control after CD70 blockade during chronic viral infection. ELISA was performed for detection of LCMV-specific IgG titers from serum at day 21 postinfection. Sera from an Armstrong-infected mouse at day 40 postinfection (memory) and from a naïve mouse were included as positive and negative controls, respectively. Data are from one representative experiment.