Implications of Resident Memory T Cells for Transplantation.

Recent studies have established resident memory T cells (TRM ) as the dominant memory lymphocyte population surveying most nonlymphoid tissues. Unlike other memory T cell lineages, TRM do not recirculate through blood and are permanently confined to their tissue of residence. TRM orchestrate local immune responses and have been shown to accelerate local pathogen control in many experimental infection models. Here we briefly summarize recent advances in TRM differentiation, maintenance, and their protective function. While little is known, we have speculated on the potential implications of TRM for transplantation biology. Areas of emphasis include the role of passenger TRM in controlling latent viral recrudescence in donor organs, donor TRM as a source of graft-versus-host disease, the ability of TRM to potently induce inflammation through sensing and alarm functions, and differentiation of host T cells into TRM in response to local cues inside the allograft. Further investigation of TRM in the context of transplantation might identify therapeutic targets to prolong graft survival.

A critical role for CD40-CD40 ligand interactions in amplification of the mucosal CD8 T cell response.

The role of CD40 ligand (CD40L) in CD8 T cell activation was assessed by tracking antigen-specific T cells in vivo using both adoptive transfer of T cell receptor transgenic T cells and major histocompatibility complex (MHC) class I tetramers. Soluble antigen immunization induced entry of CD8 cells into the intestinal mucosa and cytotoxic T lymphocyte (CTL) differentiation, whereas CD8 cells in secondary lymphoid tissue proliferated but were not cytolytic. Immunization concurrent with CD40L blockade or in the absence of CD40 demonstrated that accumulation of CD8 T cells in the mucosa was CD40L dependent. Furthermore, activation was mediated through CD40L expressed by the CD8 cells, since inhibition by anti-CD40L monoclonal antibodies occurred after adoptive transfer to CD40L-deficient mice. However, mucosal CD8 T cells in normal and CD40(-/-) mice were equivalent killers, indicating that CD40L was not required for CTL differentiation. Appearance of virus-specific mucosal, but not splenic, CD8 cells also relied heavily on CD40-CD40L interactions. The mucosal CTL response of transferred CD8 T cells was MHC class II and interleukin 12 independent. The results established a novel pathway of direct CD40L-mediated CD8 T cell activation.

Developing an HIV cytotoxic T-lymphocyte vaccine: issues of CD8 T-cell quantity, quality and location.

Issues of quantity, quality and location impact the ability of CD8 T cells to mediate protection from infection. These issues are considered in light of human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) vaccination. Methods are reviewed that result in 100- to 1000-fold higher frequencies of vaccine-specific memory CD8 T cells than that achieved by current HIV/SIV vaccine approaches. Data demonstrating that location within mucosal tissues has a direct impact on memory CD8 T-cell function are discussed. Arguments are made that establishing memory CD8 T cells within mucosal sites of transmission, a priori to natural infection, may be essential for conferring optimal and rapid protection. Lastly, it is proposed that heterologous prime-boost vaccination with recombinant live replicating vectors, which has the potential to induce tremendous numbers of cytolytic memory CD8 T cells within mucosal tissues, would provide a far more stringent test of the hypothesis that memory CD8 T cells could, in principal, form the basis for a preventative HIV vaccine.

Preferential localization of effector memory cells in nonlymphoid tissue.

Many intracellular pathogens infect a broad range of host tissues, but the importance of T cells for immunity in these sites is unclear because most of our understanding of antimicrobial T cell responses comes from analyses of lymphoid tissue. Here, we show that in response to viral or bacterial infection, antigen-specific CD8 T cells migrated to nonlymphoid tissues and were present as long-lived memory cells. Strikingly, CD8 memory T cells isolated from nonlymphoid tissues exhibited effector levels of lytic activity directly ex vivo, in contrast to their splenic counterparts. These results point to the existence of a population of extralymphoid effector memory T cells poised for immediate response to infection.

Induction of vaginal-resident HIV-specific CD8 T cells with mucosal prime-boost immunization.

Tissue-resident memory (TRM) CD8 T cells survey a range of non-lymphoid mucosal tissues where they rapidly mediate clearance of viral infections at the entry portals. Vaccines that establish CD8 TRM cells in the cervicovaginal mucosa hold promise for effective immunity against sexually transmitted HIV. We demonstrate that HIV-specific CD8 TRM cells can be established in the murine vaginal mucosa using a combined intranasal and intravaginal mucosal immunization with recombinant influenza-HIV vectors. Using in situ tetramer immunofluorescence microscopy, we found that this mucosally administered prime-boost immunization also resulted in the durable seeding of CD8 T cells in the frontline vaginal epithelial compartment as opposed to the vaginal submucosa. Upon cognate antigen recognition within the vaginal mucosa, these HIV-specific CD8 TRM cells rapidly initiated a tissue-wide state of immunity. The activation of HIV-specific CD8 TRM cells resulted in the upregulation of endothelial vessel addressin expression and substantial recruitment of both adaptive and innate immune cells in the vaginal mucosa. These findings suggest that the epithelial localization of HIV-specific CD8 TRM cell populations and their capacity to rapidly activate both arms of the immune system could significantly augment frontline defenses against vaginal HIV infection.

CD4(+) T-cell survival in the GI tract requires dectin-1 during fungal infection.

Dectin-1 is an innate antifungal C-type lectin receptor necessary for protective antifungal immunity. We recently discovered that Dectin-1 is involved in controlling fungal infections of the gastrointestinal (GI) tract, but how this C-type lectin receptor mediates these activities is unknown. Here, we show that Dectin-1 is essential for driving fungal-specific CD4(+) T-cell responses in the GI tract. Loss of Dectin-1 resulted in abrogated dendritic cell responses in the mesenteric lymph nodes (mLNs) and defective T-cell co-stimulation, causing substantial increases in CD4(+) T-cell apoptosis and reductions in the cellularity of GI-associated lymphoid tissues. CD8(+) T-cell responses were unaffected by Dectin-1 deficiency. These functions of Dectin-1 have significant implications for our understanding of intestinal immunity and susceptibility to fungal infections.

Differentiation of CD8 T cells in response to acute and chronic viral infections: implications for HIV vaccine development.

Successful HIV vaccine strategies will likely require the induction of robust cellular immune responses, in addition to strong humoral responses. Unfortunately, there is no clear molecular definition of an effective HIV-specific CD8 T cell response. In this review, we discuss the differentiation of CD8 T cells in response to acute and chronic viral infections. We then apply concepts derived from these studies to predict the desirable characteristics of HIV-specific CD8 T cell memory.

Direct analysis of the dynamics of the intestinal mucosa CD8 T cell response to systemic virus infection.

The CD8 T cell response to vesicular stomatitis virus infection was characterized in the spleen and intestinal mucosa using MHC tetramers. Surprisingly, the primary response persisted in the lamina propria long after the splenic response had declined. Furthermore, the response was characterized by a protracted effector phase in which cytolytic activity in the lamina propria, but not in the spleen, was maintained. The appearance of Ag-specific cells in the intestinal mucosa was largely, though not exclusively, a result of beta(7) integrin-mediated migration. Infection with Listeria monocytogenes or with vaccinia virus also led to sustained mucosal responses. After reinfection of vesicular stomatitis virus-primed mice with a serotypically distinct virus, a sustained recall response was detected in all tissues. In CD40(-/-) mice, the mucosal, but not the splenic, response was compromised, resulting in diminished mucosal memory. The recall response was CD40 independent and correlated with memory levels, indicating that the mucosal and systemic responses operated independently. These findings illustrated the integrated yet distinct nature of systemic vs mucosal immune responses.

Organ-specific regulation of the CD8 T cell response to Listeria monocytogenes infection.

The intestinal mucosal CD8 T cell response to infection with Listeria monocytogenes was measured using MHC class I tetramers and was compared with the response in peripheral blood, secondary lymphoid tissue, and liver. To assess the vaccination potential of Listeria and to analyze responses in C57BL/6 mouse strains, a recombinant Listeria expressing OVA (rLM-ova) was generated. The response peaked at 9 days postinfection with a much larger fraction of the intestinal mucosa and liver CD8 T cell pool OVA specific, as compared with the spleen. However, these differences were not linked to bacterial titers in each site. The higher responses in lamina propria and liver resulted in a larger CD8 memory population in these tissues. Furthermore, the level of memory induced was dependent on infectious dose and inversely correlated with the magnitude of the recall response after oral challenge. Recall responses in the tissues were most robust in the lamina propria and liver, and reactivated Ag-specific T cells produced IFN-gamma. Infection of CD40- or MHC class II-deficient mice induced poor CD8 T cell responses in the intestinal mucosa, but only partially reduced responses in the spleen and liver. Overall, the results point to novel pathways of tissue-specific regulation of primary and memory antimicrobial CD8 T cell responses.