It is, however, unclear whether these Abs have any impact on virus elimination. In the current study, we have addressed this selleck products question by infecting B-cell-sufficient mice with an impaired ability to produce antigen-specific Abs with low doses of LCMV strains that
differ in their replication speed. The results revealed that the requirement for adaptive humoral immunity to control the infection is dependent on the replicative capacity of the viral strains used. Ab transfer experiments further demonstrated that nonneutralizing NP-specific IgG Abs were capable of accelerating virus elimination in vivo. Surprisingly, these Abs functioned in an Fcγ receptor (FcγR) and C3 complement-independent manner. To overcome the caveats of mice lacking B cells, B-cell-sufficient MD4 mice were used. MD4 mice express a transgenic B-cell receptor specific for hen egg lysozyme and due to allelic exclusion, their B-cell repertoire is compromised . For our experiments, we used the LCMV strains Armstrong, WE, and Docile, which differ in their replication speed (Docile > WE > Armstrong) . MD4 mice were first infected with the slowly replicating LCMV strain Armstrong using a low virus infection dose (200 PFU). This induced a strong GP33- and NP396-specific
CD8+ T-cell response and marked upregulation of the effector cell marker killer lectin-like receptor G1 (KLRG1) on CD8+ T cells similar as in B6 wild-type mice (Fig. 1A). As in wild-type mice, virus was completely cleared in spleen, liver, and lungs of MD4 mice at day 8 postinfection (p.i.) (Fig. 1B). Androgen Receptor antagonist The same result was obtained with IgMi mice, which are severely impaired in the production of soluble Abs due to a mutated IgH gene locus  (Supporting Information Fig. 1). These data demonstrate that MD4 and IgMi mice were not inherently impaired in mounting a potent LCMV-specific CD8+ T-cell response and that an adaptive Ab response was not required to control LCMV Armstrong infection. When the faster replicating LCMV strain WE was used, we observed a decrease in KLRG1 induction
and fewer GP33-specific CD8+ T cells in MD4 compared with B6 wild-type mice at day 14 p.i. (Fig. 1C). Virus elimination MTMR9 in the spleen was delayed, nevertheless, virus was cleared in these mice as well (Fig. 1D, left). Similar to MD4 mice, virus clearance was also delayed in IgMi mice (Fig. 1D, right). Thus, after LCMV WE infection, the virus-specific CD8+ T-cell response and virus elimination were delayed in the absence of an Ab response. Most strikingly, infection of MD4 mice with the fast replicating LCMV strain Docile led to classical signs of CD8+ T-cell exhaustion indicated by low KLRG1 expression, strongly decreased IFN-γ production and significant expression of the exhaustion markers, PD-1 and 2B4 (Fig. 2A and B). LCMV Docile infected B6 wild-type mice mounted a vigorous CD8+ T-cell response characterized by high-KLRG1 expression and potent IFN-γ production.