Behazine Combadiere

Distinct Time Effects of Vaccination on Long-Term Proliferative and IFN-γ–producing T Cell Memory to Smallpox in Humans

Residual immunity to the smallpox virus raises key questions about the persistence of long-term immune memory in the absence of antigen, since vaccination ended in 1980. IFN-γ–producing effector–memory and proliferative memory T cells were compared in 79 vaccinees 13–25 yr after their last immunization and in unvaccinated individuals. Only 20% of the vaccinees displayed both immediate IFN-γ–producing effector–memory responses and proliferative memory responses at 6 d; 52.5% showed only proliferative responses; and 27.5% had no detectable vaccinia-specific responses at all. Both responses were mediated by CD4 and CD8 T cells. The vaccinia-specific IFN-γ–producing cells were composed mainly of CD4Pos CD45RANeg CD11aHi CD27Pos and CCR7Neg T cells. Their frequency was low but could be expanded in vitro within 7 d. Time since first immunization affected their persistence: they vanished 45 yr after priming, but proliferative responses remained detectable. The number of recalls did not affect the persistence of residual effector–memory T cells. Programmed revaccination boosted both IFN-γ and proliferative responses within 2 mo of recall, even in vaccinees with previously undetectable residual effector–memory cells. Such long-term maintenance of vaccinia-specific immune memory in the absence of smallpox virus modifies our understanding of the mechanism of persistence of long-term memory to poxviruses and challenges vaccination strategies.

Autocrine Feedback Death and the Regulation of Mature T Lymphocyte Antigen Responses

Antigen-induced T cell death is an important regulatory mechanism in the peripheral immune system. Evidence suggests that this process depends on T cell growth-inducing lymphokines such as IL-2 and occurs in proportion to the degree of T cell receptor occupancy. Strong T cell receptor stimulation leads to the synthesis of death molecules such as Fas ligand and tumor necrosis factor that cause T cell suicide. We propose that T cell death under these circumstances is the culmination of a feedback control mechanism termed propriocidal regulation or autocrine feedback death that regulates the expansion of specific T cell clones under conditions of high lymphokine and antigen load. In a quasi-stochastic system such as the antigen receptor repertoire, feedback information may be essential for the appropriate regulation of peripheral immune responses. Our understanding of this feedback mechanism affords a means to manipulate antigen-specific T cell death in vivo. The application of this approach to the therapy of T cell-medicated immunological diseases is discussed.

Control of vaccinia virus skin lesions by long-term-maintained IFN-γ + TNF-α + effector/memory CD4 + lymphocytes in humans

Vaccinia virus (VV) vaccination is used to immunize against smallpox and historically was considered to have been successful if a skin lesion formed at the vaccination site. While antibody responses have been widely proposed as a correlate of efficacy and protection in humans, the role of cellular and humoral immunity in VV-associated skin lesion formation was unknown. We therefore investigated whether long-term residual humoral and cellular immune memory to VV, persisting 30 years after vaccination, could control VV-induced skin lesion in revaccinated individuals. Here, we have shown that residual VV-specific IFN-gamma+TNF-alpha+ or IFN-gamma+IL-2+ CD4+ lymphocytes but not CD8+ effector/memory lymphocytes expressing a skin-homing marker are inversely associated with the size of the skin lesion formed in response to revaccination. Indeed, high numbers of residual effector T cells were associated with lower VV skin lesion size after revaccination. In contrast, long-term residual VV-specific neutralizing antibody (NAbs) titers did not affect skin lesion formation. However, the size of the skin lesion strongly correlated with high levels of NAbs boosted after revaccination. These findings demonstrate a potential role for VV-specific CD4+ responses at the site of VV-associated skin lesion, thereby providing new insight into immune responses at these sites and potentially contributing to the development of new approaches to measure the efficacy of VV vaccination.

CX3CR1 deficiency promotes muscle repair and regeneration by enhancing macrophage ApoE production.

Muscle injury triggers inflammation in which infiltrating mononuclear phagocytes are crucial for tissue regeneration. The interaction of the CCL2/CCR2 and CX3CL1/CX3CR1 chemokine axis that guides phagocyte infiltration is incompletely understood. Here, we show that CX3CR1 deficiency promotes muscle repair and rescues Ccl2−/− mice from impaired muscle regeneration as a result of altered macrophage function, not infiltration. Transcriptomic analysis of muscle mononuclear phagocytes reveals that Apolipoprotein E (ApoE) is upregulated in mice with efficient regeneration. ApoE treatment enhances phagocytosis by mononuclear phagocytes in vitro, and restores phagocytic activity and muscle regeneration in Ccl2−/− mice. Because CX3CR1 deficiency may compensate for defective CCL2-dependant monocyte recruitment by modulating ApoE-dependent macrophage phagocytic activity, targeting CX3CR1 expressed by macrophages might be a powerful therapeutic approach to improve muscle regeneration.

Mature T lymphocyte apoptosis in the healthy and diseased immune system

We have been studying a feedback regulatory mechanism termed propriocidal regulation that induces mature peripheral T cells to undergo apoptosis during an antigen response. We proposed this mechanism in order to account for two observations. First, we observed that mature T lymphocytes can be triggered to undergo apoptosis following T cell receptor (TCR) ligation 1,2, for a reviews see 3, 4. This finding challenged the prevailing idea that only immature T cells in the thymus could exhibit an apoptotic response to TCR stimulation. Second, we made the surprising observation that interleukin-2 (IL-2) was the principal influence that caused peripheral T lymphocytes to become susceptible to TCR-induced apoptosis1. This led to the notion that antigen-induced death was the end-result of a feedback loop. We conceived that strong, repeated antigen stimulation would first initiate a robust proliferative reaction and then induce the death of T cells following their effector response. This would decrease the number of specifically-responding T cells and the magnitude of the response to subsequent antigen challenge. The consequence of this feedback loop is that an unregulated geometric expansion of activated T lymphocytes and their attendant toxicities would be prevented. Thus, propriocidal regulation entails immune regulation by the programmed cell death of mature T cells. This provides a means for antigen-specific, extrathymic immunological tolerance.

Macrophages of distinct origins contribute to tumor development in the lung

Tissue-resident macrophages can self-maintain without contribution of adult hematopoiesis. Herein we show that tissue-resident interstitial macrophages (Res-TAMs) in mouse lungs contribute to the pool of tumor-associated macrophages (TAMs) together with CCR2-dependent recruited macrophages (MoD-TAMs). Res-TAMs largely correlated with tumor cell growth in vivo, while MoD-TAMs accumulation was associated with enhanced tumor spreading. Both cell subsets were depleted after chemotherapy, but MoD-TAMs rapidly recovered and performed phagocytosis-mediated tumor clearance. Interestingly, anti-VEGF treatment combined with chemotherapy inhibited both Res and Mod-TAM reconstitution without affecting monocyte infiltration and improved its efficacy. Our results reveal that the developmental origin of TAMs dictates their relative distribution, function, and response to cancer therapies in lung tumors.