Recipient mucosal-associated invariant T cells control GVHD within the colon

Mucosal-associated invariant T (MAIT) cells are a unique innate-like T cell subset that responds to a wide array of bacteria and yeast through recognition of riboflavin metabolites presented by the MHC class I–like molecule MR1. Here, we demonstrate using MR1 tetramers that recipient MAIT cells are present in small but definable numbers in graft-versus-host disease (GVHD) target organs and protect from acute GVHD in the colon following bone marrow transplantation (BMT). Consistent with their preferential juxtaposition to microbial signals in the colon, recipient MAIT cells generate large amounts of IL-17A, promote gastrointestinal tract integrity, and limit the donor alloantigen presentation that in turn drives donor Th1 and Th17 expansion specifically in the colon after BMT. Allogeneic BMT recipients deficient in IL-17A also develop accelerated GVHD, suggesting MAIT cells likely regulate GVHD, at least in part, by the generation of this cytokine. Indeed, analysis of stool microbiota and colon tissue from IL-17A–/– and MR1–/– mice identified analogous shifts in microbiome operational taxonomic units (OTU) and mediators of barrier integrity that appear to represent pathways controlled by similar, IL-17A–dependent mechanisms. Thus, MAIT cells act to control barrier function to attenuate pathogenic T cell responses in the colon and, given their very high frequency in humans, likely represent an important population in clinical BMT

Donor colonic CD103(+) dendritic cells determine the severity of acute graft-versus-host disease

The primacy of the gastrointestinal (GI) tract in dictating the outcome of graft-versus-host disease (GVHD) is broadly accepted; however, the mechanisms controlling this effect are poorly understood. Here, we demonstrate that GVHD markedly enhances alloantigen presentation within the mesenteric lymph nodes (mLNs), mediated by donor CD103(+)CD11b(-) dendritic cells (DCs) that migrate from the colon under the influence of CCR7. Expansion and differentiation of donor T cells specifically within the mLNs is driven by profound levels of alloantigen, IL-12, and IL-6 promoted by Toll-like receptor (TLR) and receptor for advanced glycation end products (RAGE) signals. Critically, alloantigen presentation in the mLNs imprints gut-homing integrin signatures on donor T cells, leading to their emigration into the GI tract where they mediate fulminant disease. These data identify a critical, anatomically distinct, donor DC subset that amplifies GVHD. We thus highlight multiple therapeutic targets and the ability of GVHD, once initiated by recipient antigen-presenting cells, to generate a profound, localized, and lethal feed-forward cascade of donor DC-mediated indirect alloantigen presentation and cytokine secretion within the GI tract.Motoko Koyama, Melody Cheong, Kate A. Markey, Kate H. Gartlan, Rachel D. Kuns, Kelly R. Locke, Katie E. Lineburg, Bianca E. Teal, Lucie Leveque-El mouttie, Mark D. Bunting, Slavica Vuckovic, Ping Zhang, Michele W.L. Teng, Antiopi Varelias, Siok-Keen Tey, Leesa F. Wockner, Christian R. Engwerda, Mark J. Smyth, Gabrielle T. Belz, Shaun R. McColl, Kelli P.A. MacDonald, and Geoffrey R. Hil

The Tetraspanin Protein CD37 Regulates IgA Responses and Anti-Fungal Immunity

Immunoglobulin A (IgA) secretion by plasma cells in the immune system is critical for protecting the host from environmental and microbial infections. However, the molecular mechanisms underlying the generation of IgA+ plasma cells remain poorly understood. Here, we report that the B cell–expressed tetraspanin CD37 inhibits IgA immune responses in vivo. CD37-deficient (CD37−/−) mice exhibit a 15-fold increased level of IgA in serum and significantly elevated numbers of IgA+ plasma cells in spleen, mucosal-associated lymphoid tissue, as well as bone marrow. Analyses of bone marrow chimeric mice revealed that CD37–deficiency on B cells was directly responsible for the increased IgA production. We identified high local interleukin-6 (IL-6) production in germinal centers of CD37−/− mice after immunization. Notably, neutralizing IL-6 in vivo reversed the increased IgA response in CD37−/− mice. To demonstrate the importance of CD37—which can associate with the pattern-recognition receptor dectin-1—in immunity to infection, CD37−/− mice were exposed to Candida albicans. We report that CD37−/− mice are evidently better protected from infection than wild-type (WT) mice, which was accompanied by increased IL-6 levels and C. albicans–specific IgA antibodies. Importantly, adoptive transfer of CD37−/− serum mediated protection in WT mice and the underlying mechanism involved direct neutralization of fungal cells by IgA. Taken together, tetraspanin protein CD37 inhibits IgA responses and regulates the anti-fungal immune response

Bone marrow transplantation generates T cell–dependent control of myeloma in mice

Transplantation with autologous hematopoietic progenitors remains an important consolidation treatment for patients with multiple myeloma (MM) and is thought to prolong the disease plateau phase by providing intensive cytoreduction. However, transplantation induces inflammation in the context of profound lymphodepletion that may cause hitherto unexpected immunological effects. We developed preclinical models of bone marrow transplantation (BMT) for MM using Vk*MYC myeloma-bearing recipient mice and donor mice that were myeloma naive or myeloma experienced to simulate autologous transplantation. Surprisingly, we demonstrated broad induction of T cell-dependent myeloma control, most efficiently from memory T cells within myeloma-experienced grafts, but also through priming of naive T cells after BMT. CD8+ T cells from mice with controlled myeloma had a distinct T cell receptor (TCR) repertoire and higher clonotype overlap relative to myeloma-free BMT recipients. Furthermore, T cell-dependent myeloma control could be adoptively transferred to secondary recipients and was myeloma cell clone specific. Interestingly, donor-derived IL-17A acted directly on myeloma cells expressing the IL-17 receptor to induce a transcriptional landscape that promoted tumor growth and immune escape. Conversely, donor IFN-γ secretion and signaling were critical to protective immunity and were profoundly augmented by CD137 agonists. These data provide new insights into the mechanisms of action of transplantation in myeloma and provide rational approaches to improving clinical outcomes

On the mating system of the cooperatively breeding saddle-backed tamarin ( Saguinus fuscicollis )

This paper reports on 5 years of observatiors of individually marked saddle-backed tamarins ( Saguinus fuscicollis , Callitrichidae). Although callitrichids have long been presumed to have a monogamous social system, this study shows that the breeding structure of saddle-back tamarin groups is highly variable. Groups most commonly include two or more adult males and a single reproductive female, but occasionally contain only a single pair of adults, or less often, two reproductively active females and one or more males. Data on group compositions, group formations, intergroup movements and copulations show that the social and mating systems of this species are more flexible than those of any other non-human primate yet studied. Infants (usually twins) were cared for by all group members. There were two classes of helpers: young, nonreproductive individuals who helped to care for full or half siblings, and cooperatively polyandrous males who cared for infants whom they may have fathered. The observations suggest that non-reproductive helpers may benefit from their helping behavior through a combination of inclusive fitness gains, reciprocal altruism, and the value of gaining experience at parental care.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46874/1/265_2004_Article_BF00295541.pd

A comparative perspective on the evolution of tamarin and marmoset social systems

Tamarins and marmosets (callitrichids) present an unusual opportunity for study of the determinants of primate social systems, because both the mating and infant care patterns of callitrichids are variable, even within individual populations. In this paper, I briefly describe three characteristics of callitrichid social systems that distinguish them from most other primates: extensive male parental care, helping by nonreproductive individuals, and variable mating patterns. I then discuss the evolution of these characteristics and of the frequent twinning exhibited by callitrichids. I suggest that an ancestor of modern callitrichids gave birth to a single offspring at a time, mated monogamously, and had significant paternal care. The idea that males of this ancestral form must have provided paternal care, even though only single infants were born, derives from a comparison of litter/mother weight ratios in modern primate species. Twinning perhaps then evolved because of a combination of dwarfing in the callitrichid lineage, leading to higher litter/mother weight ratios, and a high infant mortality rate, and because the extensive paternal care already present facilitated the raising of twins. I propose that the helping behavior of older offspring may have coevolved with twinning, because helpers would have increased the chances of survival of twins, and the presence of twins would have increased the benefits of helping. Finally, the high costs of raising twins and the variability of group compositions, especially the fact that some groups would not have had older offspring to serve as helpers, may have selected for facultative polyandry in saddle-back tamarins ( Saguinus fuscicollis ) and perhaps in other callitrichid species. Both helping and cooperative polyandry have been extensively studied in bird species, and I apply some of the conclusions of these studies to the discussion of the evolution of callitrichid social systems.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44556/1/10764_2005_Article_BF02193696.pd

Microhabitat associations and seedling bank dynamics in a neotropical forest

We conducted a rigorous test of tropical tree seedling microhabitat differentiation by examining microhabitat associations, survival and growth of established seedlings of ten tropical tree species representing a four-factor gradient in seed size. Eight microhabitat variables describing soil and light conditions were measured directly adjacent to each of 588 seedlings within twelve 10×100 m belt transects at Paracou, French Guiana, and at 264 reference points along the transects. From these measurements, we defined three principal components describing soil richness, soil softness and canopy openness. Six of ten species (in 9 of 30 total cases) were distributed non-randomly with respect to microhabitat along at least one principal component. However, few species demonstrated clear microhabitat specialization. All shifts in distribution relative to reference points were in the same direction (richer, softer soil). Furthermore, of 135 pairwise comparisons among the species, only 7 were significantly different. More than three-fourths of all seedlings (75.3%) survived over the 2-year monitoring period, but survival rates varied widely among species. In no case was the probability of survival influenced by any microhabitat parameter. Relative height growth rates for the seedlings over 2 years varied from −0.031 cm cm −1  year −1 ( Dicorynia guianensis , Caesalpiniaceae) to 0.088 cm cm −1  year −1 ( Virola michelii , Myristicaceae). In only 4 of 30 cases was height growth significantly associated with one of the three principal components. Because the conditions in this study were designed to maximize the chance of finding microhabitat differentiation among a group of species differing greatly in life history traits, the lack of microhabitat specialization it uncovered suggests that microhabitat partitioning among tropical tree species at the established seedling stage is unlikely to contribute greatly to coexistence among these species.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47708/1/442_2004_Article_1691.pd