CD80 and CD86 Control Antiviral CD8 ⁺ T-Cell Function and Immune Surveillance of Murine Gammaherpesvirus 68

Abstract

The interactions between CD80 and CD86 on antigen-presenting cells and CD28 on T cells serve as an important costimulatory signal in the activation of T cells. Although the simplistic two-signal hypothesis has been challenged in recent years by the identification of different costimulators, this classical pathway has been shown to significantly impact antiviral humoral and cellular immune responses. How the CD80/CD86-CD28 pathway affects the control of chronic or latent infections has been less well characterized. In this study, we investigated its role in antiviral immune responses against murine gammaherpesvirus 68 (MHV-68) and immune surveillance using CD80/CD86 ؊/؊ mice. In the absence of CD80/CD86, primary antiviral CD8 ؉ T-cell responses and the induction of neutralizing antibodies were severely impaired. During long-term immune surveillance, the virus-specific CD8 ؉ T cells were impaired in IFN-␥ production and secondary expansion and exhibited an altered phenotype. Surprisingly, a low level of viral reactivation in the lung was observed, and this effect was independent of CD28 and CTLA-4. Thus, CD80 and CD86, signaling through CD28 and possibly another unidentified receptor, are required for optimal immune surveillance and antiviral immune responses to murine gammaherpesvirus.

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

“…Numbers of epitope-specific donor LCMV-specific CD8 + T cells were determined; results are presented as averages 6 SD (n = 4 mice/group). (18,21). However, considering that LCMV has always been set apart as a virus that requires little or no costimulation, the present results are important in indicating that costimulation is essential at both stages of infection even when this virus is involved; that is, there seems to be no exceptions to this rule.…”

“…Consequently, these results indicate that the absence of B7.1/B7.2 has a more profound impact on the LCMV-specific immune response than does the lack of CD28, and the results may therefore suggest that there are additional stimulatory receptors for B7.1/B7.2 besides CD28. A few other studies have pointed toward the same conclusion (19)(20)(21), but so far no such receptor has been unequivocally identified.…”

“…In view of the fact that these issues had not been optimally dealt with in earlier studies on LCMV infection, we considered it important to revisit the role of CD28-B7 in inducing and maintaining LCMV-specific CD8 T cell memory, with the reason being that it would be very important to know if certain viruses would have the capacity to induce not only initial T cell activation, but also completely normal memory differentiation in the absence of this key costimulatory interaction. Our interest was further fueled by a few recent reports suggesting that there might be other stimulatory receptors for B7 than CD28 (19)(20)(21) and that earlier studies of the LCMV infection might have failed in finding a key role for B7 costimulation, because these studies had been performed in CD28 mice have no obvious phenotype following infection with MHV68, T cell-dependent immune surveillance eventually completely collapses in MHC class II-deficient mice, and, interestingly, analysis of B7.1/B7.2 2/2 mice revealed that these mice lay between these two extremes. This is similar to the situation in mice infected with moderate doses of rapidly invasive strains of LCMV, where the infection is efficiently controlled in CD28-deficient mice (17) but leads to late recrudescence of viremia and severe disease in MHC class II-deficient mice (22).…”

Detection of Anti-Yellow Fever Virus Immunoglobulin M Antibodies at 3–4 Years Following Yellow Fever Vaccination

“…[20][21][22] A third possible explanation for prolonged IgM antibody synthesis is an incomplete class switching either caused by alterations in the vaccine virus because of the attenuation process or potential interference of the vaccine virus in the regulation or recognition of molecules needed for class switching. 23,24 Finally, subsequent exposure to YF virus or a related flavivirus could have caused IgM antibodies to persist or reform after infection. 25 We did not, however, find a significant association between being YF IgM positive and potential subsequent flavivirus exposure (e.g., travel to a YF or dengue-endemic area or flavivirus vaccination).…”

Control of Memory CD8+ T Cell Differentiation by CD80/CD86-CD28 Costimulation and Restoration by IL-2 during the Recall Response

“…Costimulation, however, is considered to be dispensable for memory T cell responses. This well-established concept stems mainly from studies of memory CD4 ϩ T cell responses in vitro (34,35), as well as infection of CD28 Ϫ/Ϫ mice with lymphocytic choriomeningitis virus (LCMV) responses to influenza virus, Listeria monocytogenes, Salmonella typhimurium, Toxoplasma gondii, and murine gammaherpesvirus 68 (MHV-68) are impaired in the absence of CD28 costimulation (12,13,19,20,22,36,37). Whether these observations indicate requirements for CD28 costimulation during the primary response or during the recall response is not clear and whether CD28 costimulation affects the phenotype and function of memory CD8 ϩ T cells has not been investigated in detail.…”