Biomedical subjects

Leo Lefrançois

Publications and source records attributed to Leo Lefrançois.

At least 19 recordsLinked to original sources

PubMed2006

Persistent antigen presentation after acute vesicular stomatitis virus infection.

Long-term antigen expression is believed to play an important role in modulation of T-cell responses to chronic virus infections. However, recent studies suggest that immune responses may occur late after apparently acute infections. We have now analyzed the CD8 T-cell response to vesicular stomatitis virus (VSV), which is thought to cause to an infection characterized by rapid virus clearance by innate and adaptive immune system components. Unexpectedly, virus-encoded antigen was detectable more than 6 weeks after intranasal VSV infection in both draining and nondraining lymph nodes by adoptively transferred CD8 T cells. Infection with Listeria monocytogenes expressing the same antigen did not result in prolonged antigen presentation. Weeks after VSV infection, discrete T-cell clustering with dendritic cells within the lymph node was observed after transfer of antigen-specific CD8 T cells. Moreover, memory CD8 T cells as defined by phenotype and function were generated from naïve CD8 T cells entering the response late after infection. These findings suggested that protracted antigen presentation after an apparently acute virus infection may contribute to an ongoing antiviral immune response.

Acute Disease↗

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

Combined IL-15/IL-15Ralpha immunotherapy maximizes IL-15 activity in vivo.

IL-15 has substantial potential as an immunotherapeutic agent for augmenting immune responses. However, the activity of IL-15 is mediated by a unique mechanism in which the cytokine is transpresented by cell-bound high-affinity IL-15Ralpha to target cells expressing the IL-15Rbeta and the common gamma-chain. Thus, the efficacy of administered IL-15 alone may be limited by the availability of free IL-15Ralpha. We now show that administration of soluble IL-15/IL-15Ralpha complexes greatly enhanced IL-15 half-life and bioavailability in vivo. Treatment of mice with this complex, but not with IL-15 alone, resulted in robust proliferation of memory CD8 T cells, NK cells, and NK T cells. The activity of the complex required IL-15Rbeta, but not IL-15Ralpha, expression by the responding cells and was IL-7-independent. Interestingly, IL-15/IL-15Ralpha immunotherapy also caused naive CD8 T cell activation and development into effector cells and long-term memory T cells. Lastly, complexed IL-15, as compared with IL-15 alone, dramatically reduced tumor burden in a model of B16 melanoma. These findings hold significant importance for the use of IL-15 as a potential adjuvant/therapeutic and inducer of homeostatic proliferation, without the necessity for prior immunodepletion.

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

CD4 T cells inhibit the CD8 T cell response during low-dose virus infection.

CD4 T cells are not thought to play a significant role in generating an effective primary CD8 T cell response to most viral infections. We have challenged this view by demonstrating that antigen-specific CD4 T cells can indeed suppress the proliferation of antigen-specific naive CD8 T cells in response to low doses of vesicular stomatitis virus. This finding is in contrast to the established observations that at high antigen loads CD4 T cells play little role in generating CD8 T cell responses, and that in non-infectious model systems CD4 T cells actually help the CD8 T cell response. Our results suggest that at low infectious doses, CD4 T cells play a much larger role in controlling infections than previously appreciated.

Animals↗

PubMed2006

Dendritic cell-T cell interactions in the generation and maintenance of CD8 T cell memory.

Dendritic cells (DCs) are the critical antigen-presenting cells involved in initiating CD8 T cell responses to microbial and viral pathogens. Hence the generation of memory T cells from naïve T cells is intricately intertwined with DCs at every level. This review broadly addresses DC-CD8 T cell interactions that result in the generation and maintenance of CD8 memory T cells.

Animals↗

PubMed2006

Evidence that a significant number of naive T cells enter non-lymphoid organs as part of a normal migratory pathway.

Only activated and effector memory T cells are thought to access non-lymphoid tissues. In contrast, naive T cells are thought to circulate only between the blood, lymph and secondary lymphoid organs. We examined the phenotype of endogenous T cells in various non-lymphoid organs and showed that a subset of cells exhibited an apparently naive phenotype and were functionally inactive. FTY720 treatment selectively depleted this population from the non-lymphoid tissues. In addition, RAG-deficient TCR transgenic CD4 and CD8 T cells were present in non-lymphoid tissues in bone marrow chimeric mice and in situ imaging analysis revealed their location in the parenchymal tissues. Moreover, migration of TCR transgenic T cells to non-lymphoid tissues after adoptive transfer was pertussis-toxin resistant. Overall, the results suggest that naive T cells may circulate through non-lymphoid tissues as part of their normal migratory pathway.

Animals↗

PubMed2006

Residual antigen presentation after influenza virus infection affects CD8 T cell activation and migration.

Activated virus-specific CD8 T cells remain in the lung airways for several months after influenza virus infection. We show that maintenance of this cell population is dependent upon the route of infection and prolonged presentation of viral antigen in the draining lymph nodes (DLN) of the respiratory tract. The local effects on T cell migration have been examined. We show retention of virus-specific CD8 T cells in the mediastinal lymph node (MLN) and continuing recruitment of blood-borne migrants into the lung airways during antigen presentation. These data show that antigen that is retained after pulmonary influenza virus infection controls the migratory pattern and activation state of virus-specific CD8 T cells near the site of virus amplification.

Animals↗

PubMed2006

Persistence and responsiveness of immunologic memory in the absence of secondary lymphoid organs.

Secondary lymphoid organs (SLOs) promote primary immune responses by recruiting naive lymphocytes and activated APCs. However, their role in the persistence or responsiveness of memory lymphocytes is unclear. We tested whether memory cells were maintained and could respond to challenge in the absence of SLOs. We found that influenza-specific CD8 cells in the lung acquired a memory phenotype, underwent homeostatic proliferation, recirculated through nonlymphoid tissues, and responded to and cleared a challenge infection in the complete absence of SLOs. Similarly, influenza-specific virus-neutralizing antibody was generated and maintained in the absence of SLOs. Inducible bronchus-associated lymphoid tissue (iBALT) was also formed in the lungs of previously infected mice and may provide a niche for the maintenance of memory cells at the local level. These data show that SLOs are dispensable for the maintenance of immunologic memory and directly demonstrate the utility of local tissues, such as iBALT, in secondary immune responses.

Animals↗

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↗

PubMed2006

Development, trafficking, and function of memory T-cell subsets.

The precise mechanisms that govern memory T-cell lineage commitment during an immune response continue to be the subject of intense scrutiny. The existence of memory T-cell subsets defined by location, function, and phenotype adds an additional layer of complexity to the overall memory T-cell population. In this review, the integration of memory subset development and migration and the functional consequences of specific tissue localization are discussed.

Animals↗

PubMed2006

Intestinal and pulmonary mucosal T cells: local heroes fight to maintain the status quo.

Mucosal immunity in the lung and intestine is controlled by complex multifaceted systems. While mucosal T cells are essential for protection against invading pathogens owing to their proximity to the outside world, powerful systems must also be in place to harness ongoing inflammatory processes. In each site, distinct anatomical structures play key roles in mounting and executing both protective and deleterious mucosal T cell responses. Although analogies can be drawn regarding the immune systems of these two organs, there are substantial dissimilarities necessitated by unique physiologic constraints. Here, we discuss how T cell activation and effector function are generated in the mucosae.

Antigen Presentation↗

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↗

PubMed2005

The roles of interleukin-15 receptor alpha: trans-presentation, receptor component, or both?

Interleukin-15 receptor alpha (IL-15R alpha) is a high affinity IL-15 binding protein that is crucial for mediating IL-15 functions such as memory CD8 T cell proliferation and NK, NK/T cell, and intestinal intraepithelial lymphocyte development. However, the mechanism by which IL-15R alpha mediates IL-15 functions is unique among cytokines. Originally, IL-15R alpha was thought to be a component of a heterotrimeric receptor complex containing the IL-2/IL-15R beta and common gamma chains (gammaC) that were required for mediating signaling. Although IL-15R alpha may in some cases act as a component of this receptor complex, more recent evidence indicates that IL-15R alpha predominately functions by presenting IL-15 to opposing cells expressing the IL-15R betagamma signaling components. This theory is consistent with the broad, non-lymphoid expression pattern of IL-15R alpha and the evidence that IL-15R alpha expression by lymphocytes is dispensable for IL-15 action in vivo. This new concept of cytokine delivery will allow us to better understand the regulation and function IL-15.

Animals↗

PubMed2005

Dendritic cells maximize the memory CD8 T cell response to infection.

Costimulatory signals from dendritic cells (DCs) are required for naive T cells to respond to antigenic stimulation. To what extent DCs reactivate memory T cells during recall responses is not known. Here, an in vivo depletion system has been used to analyze the role of DCs in reactivating CD8 memory T cells during recall responses to three different microbial infections. We show a profound decrease in the numbers of responding memory CD8 T cells in both lymphoid and nonlymphoid tissues during the recall responses to infection with vesicular stomatitis virus, Listeria monocytogenes (Lm), or influenza virus. These data show that interaction with DCs is a major mechanism driving T cell reactivation in vivo, even during a tissue-specific infection of the respiratory tract.

Animals↗

PubMed2005

The CD8 memory T cell subsystem: integration of homeostatic signaling during migration.

The ability of memory CD8 T cells to patrol non-lymphoid tissues represents an effective method whereby proficient immunosurveillance is achieved. From the analysis of memory CD8 T cell migration in vivo, it is clear that tissue-specific factors control trafficking and residence time within tissues. We propose that at least three pools of memory CD8 T cells exist based on migratory capabilities as dictated by their location in the body. Moreover, we hypothesize that the process of acquisition of homeostatic signals in specific tissues, such as the cytokines IL-7 and IL-15, regulates the mobility of memory T cells.

Animals↗

PubMed2004

Intestinal epithelial antigen induces mucosal CD8 T cell tolerance, activation, and inflammatory response.

Intestinal autoimmune diseases are thought to be associated with a breakdown in tolerance, leading to mucosal lymphocyte activation perhaps as a result of encounter with bacterium-derived Ag. To study mucosal CD8(+) T cell activation, tolerance, and polarization of autoimmune reactivity to self-Ag, we developed a novel (Fabpl(4x at -132)-OVA) transgenic mouse model expressing a truncated form of OVA in intestinal epithelia of the terminal ileum and colon. We found that OVA-specific CD8(+) T cells were partially tolerant to intestinal epithelium-derived OVA, because oral infection with Listeria monocytogenes-encoding OVA did not elicit an endogenous OVA-specific MHC class I tetramer(+)CD8(+) T cell response and IFN-gamma-, IL-4-, and IL-5-secreting T cells were decreased in the Peyer's patches, mesenteric lymph nodes, and intestinal mucosa of transgenic mice. Adoptive transfer of OVA-specific CD8(+) (OT-I) T cells resulted in their preferential expansion in the Peyer's patches and mesenteric lymph nodes and subsequently in the epithelia and lamina propria but failed to cause mucosal inflammation. Thus, CFSE-labeled OT-I cells greatly proliferated in these tissues by 5 days posttransfer. Strikingly, OT-I cell-transferred Fabpl(4x at -132)-OVA transgenic mice underwent a transient weight loss and developed a CD8(+) T cell-mediated acute enterocolitis 5 days after oral L. monocytogenes-encoding OVA infection. These findings indicate that intestinal epithelium-derived "self-Ag" gains access to the mucosal immune system, leading to Ag-specific T cell activation and clonal deletion. However, when Ag is presented in the context of bacterial infection, the associated inflammatory signals drive Ag-specific CD8(+) T cells to mediate intestinal immunopathology.

Acute Disease↗

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↗