The Role of CD80/CD86 in Generation and Maintenance of Functional Virus-Specific CD8+ T Cells in Mice Infected with Lymphocytic Choriomeningitis Virus

Abstract

Lymphocytic choriomeningitis virus (LCMV)-specific CD8(+) T cell responses are considered to be independent of CD28-B7 costimulation. However, the LCMV-specific response has never been evaluated in B7.1/B7.2(-/-) mice. For this reason, we decided to study the T cell response in B7.1/B7.2(-/-) mice infected with two different strains of LCMV, one (Traub strain) typically causing low-grade chronic infection, and another (Armstrong clone 53b) displaying very limited capacity for establishing chronic infection. Using Traub virus we found that most B7.1/B7.2(-/-) mice were unable to rid themselves of the infection. Chronic infection was associated with a perturbed CD8(+) T cell epitope hierarchy, as well as with the accumulation of cells expressing markers of terminal differentiation and being unable to respond optimally to Ag restimulation. Examination of matched CD28(-/-) mice revealed a similar albeit less pronounced pattern of CD8(+) T cell dysfunction despite lack of virus persistence. Finally, analysis of B7.1/B7.2(-/-) mice infected with Armstrong virus revealed a scenario quite similar to that in Traub infected CD28(-/-) mice; that is, the mice displayed evidence of T cell dysfunction, but no chronic infection. Taken together, these results indicate that B7 costimulation is required for induction and maintenance of LCMV-specific CD8(+) T cell memory, irrespective of the LCMV strain used for priming. However, the erosion of CD8(+) T cell memory in B7.1/B7.2(-/-) mice was more pronounced in association with chronic infection. Finally, virus-specific T cell memory was more impaired in the absence of B7 molecules than in the absence of the CD28 receptor, supporting earlier data suggesting the existence of additional stimulatory receptors for B7

Enhanced and Sustained CD8+ T Cell Responses with an Adenoviral Vector-Based Hepatitis C Virus Vaccine Encoding NS3 Linked to the MHC Class II Chaperone Protein Invariant Chain

“…4 suggest that the AdIiNS3 vaccine induces memory T cells with good recall potential, because the majority of the epitope-specific T cell population expressed low levels of CD43, a marker of recent activation, combined with high levels of CD27 expression. This combination of phenotypic markers (CD43 low /CD27 high ) was recently found to be an indicator for a good recall potential upon a secondary challenge with Sendai virus (43) and permanent virus control in mice infected with LCMV, a virus with the potential to establish chronic infection (45). Moreover, a study comparing the response to different human viral infections including HCV suggests that Ag-experienced CD27 + CD8 + cell are early differentiated memory cells (46).…”

Multiple Layers of CD80/86-Dependent Costimulatory Activity Regulate Primary, Memory, and Secondary Lymphocytic Choriomeningitis Virus-Specific T Cell Immunity

“…In more recent work, potential problems arising from the generation of virus-specific CD8 ϩ T M populations in immunodeficient mice were circumvented by the adoptive transfer (AT) of wt CD8 ϩ T M into CD80/86 Ϫ/Ϫ hosts and/or the administration of a costimulation blockade (anti-CD28 or CTLA4Ig) specifically in the context of secondary challenges. Collectively, those studies demonstrated that influenza virus-, HSV-1-, VACV-, LCMV-, and MHV-68-specific CD8 ϩ T M primed in wt mice require signaling via the CD28-CD80/86 axis for efficient secondary expansion (10,24,25,28) and virus clearance (10,25). In addition, the generation of VACV-, MHV-68-, or LCMV-specific CD8 ϩ T M in CD28 Ϫ/Ϫ or CD80/86 Ϫ/Ϫ mice compromised their secondary reactivity after AT into wt hosts (24,28), indicating the acquisition of certain CD8 ϩ T M -intrinsic functional defects that, in the case of CD28 Ϫ/Ϫ VACV-specific CD8 ϩ T M , could be reversed only by interleukin-2 (IL-2) immune complex treatment during the recall phase (24).…”

“…Collectively, those studies demonstrated that influenza virus-, HSV-1-, VACV-, LCMV-, and MHV-68-specific CD8 ϩ T M primed in wt mice require signaling via the CD28-CD80/86 axis for efficient secondary expansion (10,24,25,28) and virus clearance (10,25). In addition, the generation of VACV-, MHV-68-, or LCMV-specific CD8 ϩ T M in CD28 Ϫ/Ϫ or CD80/86 Ϫ/Ϫ mice compromised their secondary reactivity after AT into wt hosts (24,28), indicating the acquisition of certain CD8 ϩ T M -intrinsic functional defects that, in the case of CD28 Ϫ/Ϫ VACV-specific CD8 ϩ T M , could be reversed only by interleukin-2 (IL-2) immune complex treatment during the recall phase (24). Since similar costimulation requirements also seem to apply to influenza virus-, VACV-, and LCMV-specific CD4 ϩ T M (23,25,74), it would appear that the optimal elaboration of secondary antiviral T cell immunity at large is indeed dependent on productive CD28-CD80/86 interactions.…”

“…To date, infections with multiple distinct and related viruses, escalating dosages, and various challenge routes have been employed to ascertain the role of CD28-CD80/86 costimulation preferentially in CD28 Ϫ/Ϫ mice but also complemented by analyses of CD80 Ϫ/Ϫ and/or CD86 Ϫ/Ϫ strains as well as ligand (anti-CD80/86 and CTLA-4Ig) and receptor (anti-CD28 and anti-CTLA-4) blockade. These viruses include LCMV (1,15,25,28,36,44,45,65,69,72,73,81); vesicular stomatitis virus (VSV) (1, 15, 43-45, 58, 69); vaccinia virus (VACV) (21,23,24,45,67,70) and the related ectromelia virus (ECTV) (21); influenza A virus (5,7,8,10,14,29,32,51,53,74), herpes simplex viruses (herpes simplex virus 1 [HSV-1] and HSV-2) (10,20,75,76); murine gammaherpesvirus 68 (MHV-68) (18,22,24,42,47,54); polyomavirus (PyV) (41), murine cytomegalovirus (MCMV) (2,3,17); and adenovirus …”

“…Perhaps most impressively, CD28 Ϫ/Ϫ mice were highly susceptible to lethal mousepox as a consequence of delayed and reduced CD8 ϩ T E responses in the wake of infection with the natural mouse pathogen ECTV (21). In regard to the second paradigm, although considerably less attention has been devoted to the role of CD28-CD80/86 signaling in the generation of antiviral CD4 ϩ T E immunity, the reduction of primary CD4 ϩ T E responses specific for LCMV (15,28,44,65,73), influenza virus (8), VSV (44), HSV-1 (20), and MCMV (2) observed for CD28 Ϫ/Ϫ or CD80/86 Ϫ/Ϫ mice or under conditions of CD80/86 blockade supports the concept that the effective generation of CD4 ϩ T cell immunity is critically dependent on CD28-CD80/86 costimulation. Interestingly, though, VACV-specific CD4 ϩ T E responses elicited in CD80/86 Ϫ/Ϫ mice were reported to be normal, but the possible reasons for this particular divergence from all other viral model systems remain rather speculative (23).…”