Elimination of Friend Retrovirus in the Absence of CD8⁺T Cells

Abstract

Friend retrovirus complex (FV) induces acute erythroid cell hyperplasia and massive splenomegaly followed by the emergence of fatal erythroleukemia upon inoculation into adult mice of susceptible strains (1-3). Because the disease can progress in the presence of host immune responses, FV has served as a useful model to study how retroviruses evade immune control (1,3,4). Depending on genotypes at several host loci, some strains of mice can eliminate virus-producing cells and recover from splenomegaly, while others progress rapidly to fatal pathology (1,3,5). Results from several research groups largely agree on the role of virus-neutralizing antibodies and CD4 ϩ T cells in immune control of FV infection (6-15). Natural killer cells also contribute to FV elimination and are essential for vaccine-induced protection of highly susceptible mice (8, 16). However, there are conflicting views on the role of CD8 ϩ T cells in FV control. Earlier studies associated major histocompatibility complex class I (MHC-I) alleles with spontaneous recovery from FVinduced splenomegaly, and FV-specific, CD8ϩ cytotoxic T cells were detected (1, 5). Further, the recovery in H2 b mice was abrogated when CD8 ϩ T cells were depleted (6). On the other hand, by using FV-encoded epitopes recognized by CD4 ϩ T cells as peptide vaccines, we have shown that highly susceptible (BALB/c ϫ C57BL/6)F 1 mice can still be protected from FV challenge and eliminate virus-producing cells in the absence of CD8 ϩ T cells (9). Interestingly, MHC-I genotypes influenced cytokine production from CD4 ϩ T cells upon FV infection (17, 18), indicating the possible indirect role of CD8 ϩ T cells. C57BL/6 (B6) mice lack the expression of a short form of hematopoietic cell-specific receptor tyrosine kinase, Stk, and do not develop FV-induced erythroid cell proliferation (19). Some reports have indicated that CD8 ϩ T cells are essential in controlling FV infection in B6 mice, as infectious centers at an early time point after FV infection increased upon depletion of CD8 ϩ T cells (20)(21)(22). However, infectious centers were detected in the above-described reports with monoclonal antibody 720 (23) that reacts only with the helper component of FV, Friend murine leukemia virus (F-MuLV), but not with the pathogenic component, the spleen focus-forming virus (SFFV). In our recent work (24), SFFV was eliminated from B6 mice by 2 weeks after infection, and CD8 ϩ T cell-deficient B6 mice remained resistant to FV-induced disease development. Thus, the increase of F-MuLV infectious centers after CD8 ϩ T cell depletion, albeit statistically significant, may not reflect pathologically significant changes in SFFV load.Here, we examined changes in SFFV copy numbers in CD8 ϩ T cell-deficient B6 mice after FV infection. CD8 ϩ T cell-deficient B6 mice nevertheless eliminated both F-MuLV and SFFV proviruses, though more slowly than the wild-type B6 mice did, as shown in Fig. 1. Thus, while CD8 ϩ T cells do contribute to control FV infection, they are not essential for the elimination o...

CD8 + T Cells Are Essential for Controlling Acute Friend Retrovirus Infection in C57BL/6 Mice

“…T cells contribute to control of FV infection, but are not essential for the elimination of FV in B6 [C57BL/6] mice" (1). On face value, this conclusion appears to further diminish the importance of the CD8 ϩ T cell response in recovery from retroviral infection, consistent with previous assertions by these authors that CD8 ϩ T cells are prematurely exhausted during acute FV infection (2).…”

Class Switch Recombination and Somatic Hypermutation of Virus-Neutralizing Antibodies Are Not Essential for Control of Friend Retrovirus Infection

“…In C57BL/6 (B6) mice homozygously possessing the resistant Fv2 allele (4), not only is SFFV-induced proliferation of infected erythroid progenitor cells limited, but they are also actively eliminated by cellular immune responses (5). CD4 ϩ T cells are required for SFFV elimination, while B-lymphocytes are required for F-MuLV elimination (5,6). FV-susceptible (BALB/c ϫ B6)F 1 (CB6F 1 ) mice rapidly develop splenomegaly and succumb to leukemia within 2 months postinfection (pi), but they can be protected against FV by a single immunization with an F-MuLV-encoded CD4 ϩ T cell epitope, Env 462-479 (7).…”

Reply to “CD8 + T Cells Are Essential for Controlling Acute Friend Virus Infection in C57BL/6 Mice”

“…n the letter entitled "CD8 ϩ T Cells Are Essential for Controlling Acute Friend Retrovirus Infection in C57BL/6 Mice" (1), Joedicke et al raised some questions about interpretations of the data presented in our recent letter (2). First, they point out that the lack of CD8 ϩ T cells in ␤ 2 -microglobulin (␤ 2 m)-deficient mice might be compensated for by enhanced responses of other immune cell subsets.…”

“…Unfortunately, both in the T-cell depletion papers we cited in the previous letter and this reply (3,(12)(13)(14) and in the present data utilizing CD8 knockout mice (1), the authors measured FV infectious centers only at one or two time points in the very early phase (10 to 14 days after infection). We have stated in our previous letter that mice deficient in CD8 ϩ T cells do possess higher numbers of FV proviruses than wild-type B6 mice at 14 days after infection (2). What really matters, however, is whether these viruses are eliminated through host responses at the later time points.…”