Biomedical subjects

Amanda L Marzo

Publications and source records attributed to Amanda L Marzo.

11 recordsLinked to original sources

PubMed2007

Phagocytosis of Borrelia burgdorferi and Treponema pallidum potentiates innate immune activation and induces gamma interferon production.

We examined the interactions of live and lysed spirochetes with innate immune cells. THP-1 monocytoid cells were activated to comparable extents by live Borrelia burgdorferi and by B. burgdorferi and Treponema pallidum lysates but were poorly activated by live T. pallidum. Because THP-1 cells poorly internalized live spirochetes, we turned to an ex vivo peripheral blood mononuclear cell system that would more closely reflect spirochete-mononuclear phagocyte interactions that occur during actual infection. In this system, B. burgdorferi induced significantly greater monocyte activation and inflammatory cytokine production than did borrelial lysates or T. pallidum, and only B. burgdorferi elicited gamma interferon (IFN-gamma) from NK cells. B. burgdorferi was phagocytosed avidly by monocytes, while T. pallidum was not, suggesting that the enhanced response to live B. burgdorferi was due to phagocytosis of the organism. When cytochalasin D was used to block phagocytosis of live B. burgdorferi, cytokine production decreased to levels comparable to those induced by B. burgdorferi lysates, while the IFN-gamma response was abrogated altogether. In the presence of human syphilitic serum, T. pallidum was efficiently internalized and initiated responses resembling those observed with live B. burgdorferi, including the production of IFN-gamma by NK cells. Depletion of monocytes revealed that they were the primary source of inflammatory cytokines, while dendritic cells (DCs) directed IFN-gamma production from innate lymphocytes. Thus, phagocytosis of live spirochetes initiates cell activation programs in monocytes and DCs that differ qualitatively and quantitatively from those induced at the cell surface by lipoprotein-enriched lysates. The greater stimulatory capacity of B. burgdorferi versus T. pallidum appears to be explained by the successful recognition and phagocytosis of B. burgdorferi by host cells and the ability of T. pallidum to avoid detection and uptake by virtue of its denuded outer membrane rather than by differences in surface lipoprotein expression.

Borrelia burgdorferi↗

PubMed2006

CD8 T cell recall responses are regulated by the tissue tropism of the memory cell and pathogen.

Whether memory CD8 T cells can be reactivated in nonlymphoid tissues is unclear. Using mice lacking the spleen, lymph nodes, or both, we show that the secondary T cell response, but not homeostatic maintenance of memory cells, required lymphoid tissue. Whereas primary and secondary CD8 T cell responses to vesicular stomatitis virus infection were lymph node dependent, responses to Listeria monocytogenes infection were driven primarily in the spleen. Memory cell subset reactivation was also regulated by location of the responding population and the pathogen. Thus, CD62Llow effector memory T cells (TEM) cells responded nearly as well as CD62Lhigh central memory T cells (TCM) and TCM cells after L. monocytogenes infection, and both subsets generated equivalent populations of secondary memory cells. In contrast, TCM cells, but not TEM cells, mounted a robust response to vesicular stomatitis virus infection. TCM and TEM cells also required lymphoid tissue to mount recall responses, and the bone marrow did not contribute significantly to the response of either subset. Our findings indicated that characteristics of the infectious agent and the migratory preferences of memory cells dictated the secondary lymphoid tissue requirement for the recall response to infection.

Animals↗

PubMed2006

Cutting edge: IL-7-independent regulation of IL-7 receptor alpha expression and memory CD8 T cell development.

Expression of IL-7Ralpha on a subset of Ag-specific effector CD8 T cells is believed to identify memory cell precursors. However, whether IL-7 regulates IL-7Ralpha expression in vivo and is responsible for selective survival of IL-7Ralpha(+) effector cells is unknown. Our results show that in the absence of IL-7, IL-7Ralpha expression was extinguished on the majority of CD8 T cells responding to virus infection, sustained on a subset of effector cells transitioning to memory, and expressed at high levels by memory cells. Additionally, an IL-7-deficient environment was capable of supporting bcl-2 up-regulation and memory cell development in response to virus infection. Thus, IL-7Ralpha regulation occurs independently of IL-7 in responding CD8 T cells, indicating that CD8 memory T cell precursors are not selected by IL-7/IL-7Ralpha interactions.

Adoptive Transfer↗

PubMed2006

The descent of memory T-cell subsets.

The immune system has evolved by continuously increasing its complexity to provide the host with an advantage over infectious agents. The development of immunological memory engenders long-lasting protection and lengthens the lifespan of the host. The generation of subsets of memory T cells with distinct homing and functional properties increases our defensive capabilities. However, the developmental relationship of memory T-cell subsets is a matter of debate. In this Opinion article, in light of recent developments, we suggest that it is probable that two distinct lineages comprise the memory CD8+ T-cell population generated in response to infection.

Animals↗

PubMed2005

Initial T cell frequency dictates memory CD8+ T cell lineage commitment.

Memory T cells can be divided into central memory T cell (T(CM) cell) and effector memory T cell (T(EM) cell) subsets based on homing characteristics and effector functions. Whether T(EM) and T(CM) cells represent interconnected or distinct lineages is unclear, although the present paradigm suggests that T(EM) and T(CM) cells follow a linear differentiation pathway from naive T cells to effector T cells to T(EM) cells to T(CM) cells. We show here that naive T cell precursor frequency profoundly influenced the pathway along which CD8+ memory T cells developed. At low precursor frequency, those T(EM) cells generated represented a stable cell lineage that failed to further differentiate into T(CM) cells. These findings do not adhere to the present dogma regarding memory T cell generation and provide a means for identifying factors controlling memory T cell lineage commitment.

Animals↗

PubMed2004

Fully functional memory CD8 T cells in the absence of CD4 T cells.

The role of CD4 T cells in providing help to CD8 T cells in primary and secondary responses to infection remains controversial. Using recombinant strains of virus and bacteria expressing the same Ag, we determined the requirement for CD4 T cells in endogenous CD8 T cell responses to infection with vesicular stomatitis virus and Listeria monocytogenes (LM). Depletion of CD4 T cells had no effect on the frequency of primary or secondary vesicular stomatitis virus-specific CD8 T cells in either lymphoid or nonlymphoid tissues. In contrast, the primary LM-specific CD8 T cell response was CD4 T cell dependent. Surprisingly, the LM-specific CD8 T cell recall response was also CD4 T cell dependent, which correlated with a requirement for CD40/CD40L interactions. However, concomitant inhibition of CD40L and CD4 T cell removal revealed that these pathways may be operating independently. Importantly, despite the absence of CD4 T cells during the recall response or throughout the entire response, CD8 memory T cells were functional effectors and proliferated equivalently to their "helped" counterparts. These data call into question the contention that CD4 T cells condition memory CD8 T cells during the primary response and indicate that the principal role of CD4 T cells in generating CD8 memory cells after infection is augmentation of proliferation or survival through costimulatory signals.

Animals↗

PubMed2004

Activated primary and memory CD8 T cells migrate to nonlymphoid tissues regardless of site of activation or tissue of origin.

Following activation within secondary lymphoid tissue, CD8 T cells must migrate to targets, such as infected self tissue, allografts, and tumors, to mediate contact-dependent effector functions. To test whether the pattern of migration of activated CD8 T cells was dependent on the site of Ag encounter, we examined the distribution of mouse Ag-specific CD8 T cells following local challenges. Our findings indicated that activated CD8 T cells migrated pervasively to all nonlymphoid organs irrespective of the site of initial Ag engagement. Using an adoptive transfer system, migration of nonlymphoid memory cells was also examined. Although some limited preference for the tissue of origin was noted, transferred CD8 memory T cells from various nonlymphoid tissues migrated promiscuously, except to the intestinal mucosa, supporting the concept that distinct memory pools may exist. However, regardless of the tissue of origin, reactivation of transferred memory cells resulted in widespread dissemination of new effector cells. These data indicated that recently activated primary or memory CD8 T cells were transiently endowed with the ability to traffic to all nonlymphoid organs, while memory cell trafficking was more restricted. These observations will help refine our understanding of effector and memory CD8 T cell migration patterns.

Adoptive Transfer↗

PubMed2004

Dynamics of blood-borne CD8 memory T cell migration in vivo.

Memory T cells are distributed throughout the body following infection, but the migratory dynamics of the memory pool in vivo is unknown. The ability of circulating microbe-specific memory T cells to populate lymphoid and nonlymphoid tissues was examined using adoptive transfer and parabiosis systems. While migration of memory CD8 T cells to lymph nodes and peritoneal cavity required G(i)-coupled receptor signaling, migration to the spleen, bone marrow, lung, and liver was independent of this pathway. Following parabiosis, memory T cells rapidly equilibrated into the lymphoid tissues, lung, and liver of each parabiont, implying most memory cells were not obligately tissue resident. Equilibration of memory cell populations was delayed in the brain, peritoneal cavity, and intestinal lamina propria, indicating controlled gating for entry into these tissues. In addition, memory cell migration to the lamina propria required beta7 integrins. Thus, the blood-borne T cell pool serves to maintain the homeostasis of tissue-based memory populations.

Animals↗

PubMed2003

Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells.

Cross-presentation of cell-bound Ags from established, solid tumors to CD8 cells is efficient and likely to have a role in determining host response to tumor. A number of investigators have predicted that when tumor Ags are derived from apoptotic cells either no response, due to Ag "sequestration," or CD8 cross-tolerance would ensue. Because the crucial issue of whether this happens in vivo has never been addressed, we induced apoptosis of established hemagglutinin (HA)-transfected AB1 tumors in BALB/c mice using the apoptosis-inducing reagent gemcitabine. This shrank the tumor by approximately 80%. This induction of apoptosis increased cross-presentation of HA to CD8 cells yet neither gross deletion nor functional tolerance of HA-specific CD8 cells were observed, based on tetramer analysis, proliferation of specific CD8 T cells, and in vivo CTL activity. Interestingly, apoptosis primed the host for a strong antitumor response to a second, virus-generated HA-specific signal in that administration of an HA-expressing virus after gemcitabine administration markedly decreased tumor growth compared with viral administration without gemcitabine. Thus tumor cell apoptosis in vivo neither sequesters tumor Ags nor cross-tolerizes tumor-specific CD8 cells. This observation has fundamental consequences for the development of tumor immunotherapy protocols and for understanding T cell reactivity to tumors and the in vivo immune responses to apoptotic cells.

Animals↗

PubMed2002

Tissue-level regulation of Th1 and Th2 primary and memory CD4 T cells in response to Listeria infection.

Ag-specific Th1 and Th2 cytokine-producing CD4 T cells were quantitated in secondary lymphoid and tertiary tissues following oral Listeria monocytogenes infection. Although the response to Listeria was previously believed to be predominantly Th1 like, CD4 T cells producing IL-4 or IL-5 comprised a substantial proportion of the overall primary and memory response. The frequency of IFN-gamma-, IL-4-, or IL-5-producing primary effector or memory CD4 T cells was significantly higher in lung, liver, and intestinal lamina propria (LP) as compared with spleen and lymph node. However, maximum numbers of IL-4- and IL-5-producing cells were detected in the LP several days after the peak of the Th1 response, and IL-5 production was skewed toward the mucosal tissues. Remarkably, the recall response resulted in sustained Th1 and Th2 responses in tertiary, but not lymphoid tissues and long-term retention of Th1 and Th2 memory cells in equal proportions in the LP. Finally, CD40 ligand was essential for induction of IFN-gamma in the spleen and LP, but not in the liver and lung, while the IL-4 response required CD40 ligand only in the spleen. Therefore, the rules governing the effector phenotype, and the overall magnitude of the CD4 response, are regulated at the level of individual tissues.

Animals↗

PubMed2002

Migration of primary and memory CD8 T cells.

Our results indicate that a substantial proportion of the antimicrobial CD8 and CD4 T cell response is focused in non-lymphoid tissues. This finding makes teleological sense since maximum protection against infection is better served by the widespread presence of effector and memory cells. In the case of CD8 T cells, it appears that irrespective of the site at which initial activation of naive cells occurs, the end result is production of effector cells with broad migratory capabilities. Memory T cells perhaps have more restricted migratory abilities as compared to effector cells, although this needs to be tested definitively. Our results suggest that memory CD8 T cells in the intestinal LP may not be part of the recirculating pool of memory cells, though our data does not preclude the possibility that migrants from outside the mucosa contribute to the LP memory pool. Our data also demonstrates that CD8 memory T cells in non-lymphoid tissue exhibit heightened effector function as compared to their splenic counterparts. Whether these findings indicate the existence of distinct lineages of memory cells remains to be seen. The functional abilities of migrating memory cells could be modulated by the migration process and/or by the environmental milieu of a particular tissue. Although the development of CD8 memory T cells is a complex process requiring multiple signalling pathways, we identified IL-7 as an important player in memory generation. Much further work is needed to decipher the cellular and molecular mechanisms of memory induction as well as to learn the in vivo functional significance of memory cell subsets.

Animals↗