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4-1BBL(-/-) mice exhibit normal primary CD8 T cell responses to influenza virus, but show decreased CD8 T cell numbers late in the primary response as well as decreased secondary responses. In contrast, CD28(-/-) mice are defective in initial CD8 T cell expansion. Using agonistic anti-4-1BB Ab to replace the CD28 or 4-1BB signal, we examined the timing of the required signals for CD28 vs 4-1BB costimulation. A single dose of agonistic anti-4-1BB Ab added only during priming restores the secondary CD8 T cell response in CD28(-/-) mice. Once the T cell numbers in the primary response reach a minimum threshold, a full secondary response is achieved even in the absence of CD28. In contrast, anti-4-1BB added during priming fails to correct the defective secondary response in 4-1BBL(-/-) mice, whereas addition of anti-4-1BB during challenge fully restores this response. Thus, there is a switch in costimulatory requirement from CD28 to 4-1BB during primary vs recall responses. Adoptive transfer studies show that T cells primed in 4-1BBL(-/-) or wild-type mice are equally capable of re-expansion when rechallenged in wild-type mice. These studies rule out a model in which signals delivered through 4-1BB during priming program the T cells to give a full recall response and suggest that 4-1BB-4-1BBL interactions take place at later stages in the immune response. The results indicate that anti-4-1BB or 4-1BBL therapy will be most effective during the boost phase of a prime-boost vaccination strategy.

The costimulatory protein ICOS is inducibly expressed on activated T cells. Previous results have shown that ICOS(-/-) mice are defective in germinal center formation, antibody (Ab) production and class switch as well as Th1 and Th2 cytokine production in response to protein or parasite antigens. However, ICOS-Ig failed to block antiviral Ab responses. To date the immune response to viruses has not been examined in ICOS(-/-) mice. In this report we compared antiviral Ab responses to LCMV, VSV and influenza virus in ICOS(-/-) versus wild-type mice. Our results show that ICOS is important in the Ab response to all three viruses, with greater effects on primary as compared to secondary responses. Although ICOS(-/-) mice are impaired in some immune responses following influenza infection, the effects were less severe than for CD28(-/-) mice. There was no defect in initial influenza-specific CD8 T cell expansion in ICOS(-/-) mice or in cytotoxic effector function. However, ICOS was important in maintaining CD4 cytokine production and CD8 T cell numbers late in the primary response. Upon secondary infection, ICOS(-/-) mice show wild-type levels of influenza-specific CD8 T cells, whereas CD28(-/-) mice show greatly impaired secondary CD8 T cell expansion. Overall, our results show that ICOS plays a clear role in the primary response to viruses at the level of Ab production, germinal center formation and Th cytokine production, but has diminished effects following secondary viral challenge.

In this report, we demonstrate that CD28(-/-) mice are severely impaired in the initial expansion of D(b)/NP366-374-specific CD8 T cells in response to influenza virus infection, whereas 4-1BB ligand (4-1BBL)(-/-) mice show no defect in primary T cell expansion to influenza virus. In contrast, 4-1BBL(-/-) mice show a decrease in D(b)/NP366-374-specific T cells late in the primary response. Upon secondary challenge with influenza virus, 4-1BBL(-/-) mice show a decrease in the number of D(b)/NP366-374-specific T cells compared to wild-type mice such that the level of the CD8 T cell expansion during the in vivo secondary response is reduced to the level of a primary response, with concomitant reduction of CTL effector function. In contrast, Ab responses, as well as secondary CD4 T cell responses, to influenza are unaffected by 4-1BBL deficiency. Thus, CD28 is critical for initial T cell expansion, whereas 4-1BB/4-1BBL signaling affects T cell numbers much later in the response and is essential for the survival and/or responsiveness of the memory CD8 T cell pool.