All Publications

  • Normalizing Microbiota-Induced Retinoic Acid Deficiency Stimulates Protective CD8(+) T Cell-Mediated Immunity in Colorectal Cancer. Immunity Bhattacharya, N., Yuan, R., Prestwood, T. R., Penny, H. L., DiMaio, M. A., Reticker-Flynn, N. E., Krois, C. R., Kenkel, J. A., Pham, T. D., Carmi, Y., Tolentino, L., Choi, O., Hulett, R., Wang, J., Winer, D. A., Napoli, J. L., Engleman, E. G. 2016; 45 (3): 641-655


    Although all-trans-retinoic acid (atRA) is a key regulator of intestinal immunity, its role in colorectal cancer (CRC) is unknown. We found that mice with colitis-associated CRC had a marked deficiency in colonic atRA due to alterations in atRA metabolism mediated by microbiota-induced intestinal inflammation. Human ulcerative colitis (UC), UC-associated CRC, and sporadic CRC specimens have similar alterations in atRA metabolic enzymes, consistent with reduced colonic atRA. Inhibition of atRA signaling promoted tumorigenesis, whereas atRA supplementation reduced tumor burden. The benefit of atRA treatment was mediated by cytotoxic CD8(+) T cells, which were activated due to MHCI upregulation on tumor cells. Consistent with these findings, increased colonic expression of the atRA-catabolizing enzyme, CYP26A1, correlated with reduced frequencies of tumoral cytotoxic CD8(+) T cells and with worse disease prognosis in human CRC. These results reveal a mechanism by which microbiota drive colon carcinogenesis and highlight atRA metabolism as a therapeutic target for CRC.

    View details for DOI 10.1016/j.immuni.2016.08.008

    View details for PubMedID 27590114

    View details for PubMedCentralID PMC5132405

  • An interactive reference framework for modeling a dynamic immune system SCIENCE Spitzer, M. H., Gherardini, P. F., Fragiadakis, G. K., Bhattacharya, N., Yuan, R. T., Hotson, A. N., Finck, R., Carmi, Y., Zunder, E. R., Fantl, W. J., Bendall, S. C., Engleman, E. G., Nolan, G. P. 2015; 349 (6244): 155-?
  • IMMUNOLOGY. An interactive reference framework for modeling a dynamic immune system. Science Spitzer, M. H., Gherardini, P. F., Fragiadakis, G. K., Bhattacharya, N., Yuan, R. T., Hotson, A. N., Finck, R., Carmi, Y., Zunder, E. R., Fantl, W. J., Bendall, S. C., Engleman, E. G., Nolan, G. P. 2015; 349 (6244)


    Immune cells function in an interacting hierarchy that coordinates the activities of various cell types according to genetic and environmental contexts. We developed graphical approaches to construct an extensible immune reference map from mass cytometry data of cells from different organs, incorporating landmark cell populations as flags on the map to compare cells from distinct samples. The maps recapitulated canonical cellular phenotypes and revealed reproducible, tissue-specific deviations. The approach revealed influences of genetic variation and circadian rhythms on immune system structure, enabled direct comparisons of murine and human blood cell phenotypes, and even enabled archival fluorescence-based flow cytometry data to be mapped onto the reference framework. This foundational reference map provides a working definition of systemic immune organization to which new data can be integrated to reveal deviations driven by genetics, environment, or pathology.

    View details for DOI 10.1126/science.1259425

    View details for PubMedID 26160952

    View details for PubMedCentralID PMC4537647

  • B-1a lymphocytes attenuate insulin resistance. Diabetes Shen, L., Chng, M. H., Alonso, M. N., Yuan, R., Winer, D. A., Engleman, E. G. 2015; 64 (2): 593-603


    Obesity-associated insulin resistance, a common precursor of type 2 diabetes, is characterized by chronic inflammation of tissues, including visceral adipose tissue (VAT). Here we show that B-1a cells, a subpopulation of B lymphocytes, are novel and important regulators of this process. B-1a cells are reduced in frequency in obese high-fat diet (HFD)-fed mice, and EGFP interleukin-10 (IL-10) reporter mice show marked reductions in anti-inflammatory IL-10 production by B cells in vivo during obesity. In VAT, B-1a cells are the dominant producers of B cell-derived IL-10, contributing nearly half of the expressed IL-10 in vivo. Adoptive transfer of B-1a cells into HFD-fed B cell-deficient mice rapidly improves insulin resistance and glucose tolerance through IL-10 and polyclonal IgM-dependent mechanisms, whereas transfer of B-2 cells worsens metabolic disease. Genetic knockdown of B cell-activating factor (BAFF) in HFD-fed mice or treatment with a B-2 cell-depleting, B-1a cell-sparing anti-BAFF antibody attenuates insulin resistance. These findings establish B-1a cells as a new class of immune regulators that maintain metabolic homeostasis and suggest manipulation of these cells as a potential therapy for insulin resistance.

    View details for DOI 10.2337/db14-0554

    View details for PubMedID 25249575

    View details for PubMedCentralID PMC4303967

  • In Vivo T Cell Activation Induces the Formation of CD209(+) PDL-2(+) Dendritic Cells PLOS ONE Davidson, M. G., Alonso, M. N., Kenkel, J. A., Suhoski, M. M., Gonzalez, J. C., Yuan, R., Engleman, E. G. 2013; 8 (10)

    View details for DOI 10.1371/journal.pone.0076258

    View details for Web of Science ID 000325434500056

    View details for PubMedID 24098455

  • Th17 cells induce Th1-polarizing monocyte-derived dendritic cells. Journal of immunology Davidson, M. G., Alonso, M. N., Yuan, R., Axtell, R. C., Kenkel, J. A., Suhoski, M. M., González, J. C., Steinman, L., Engleman, E. G. 2013; 191 (3): 1175-1187


    In chronically inflamed tissues, such as those affected by autoimmune disease, activated Th cells often colocalize with monocytes. We investigate in this study how murine Th cells influence the phenotype and function of monocytes. The data demonstrate that Th1, Th2, and Th17 subsets promote the differentiation of autologous monocytes into MHC class II(+), CD11b(+), CD11c(+) DC that we call DCTh. Although all Th subsets induce the formation of DCTh, activated Th17 cells uniquely promote the formation of IL-12/IL-23-producing DCTh (DCTh17) that can polarize both naive and Th17 cells to a Th1 phenotype. In the inflamed CNS of mice with Th17-mediated experimental autoimmune encephalomyelitis, Th cells colocalize with DC, as well as monocytes, and the Th cells obtained from these lesions drive the formation of DCTh that are phenotypically indistinguishable from DCTh17 and polarize naive T cells toward a Th1 phenotype. These results suggest that DCTh17 are critical in the interplay of Th17- and Th1-mediated responses and may explain the previous finding that IL-17-secreting Th cells become IFN-γ-secreting Th1 cells in experimental autoimmune encephalomyelitis and other autoimmune disorders.

    View details for DOI 10.4049/jimmunol.1203201

    View details for PubMedID 23794631

    View details for PubMedCentralID PMC3954848

  • Retinoic acid regulates the development of a gut-homing precursor for intestinal dendritic cells. Mucosal immunology Zeng, R., Oderup, C., Yuan, R., Lee, M., Habtezion, A., Hadeiba, H., BUTCHER, E. C. 2013; 6 (4): 847-856


    The vitamin A metabolite retinoic acid (RA) regulates intestinal immune responses through immunomodulatory actions on intestinal dendritic cells (DCs) and lymphocytes. Here, we show that RA also controls the generation of gut-tropic migratory DC precursors, referred to as pre-mucosal DCs (pre-μDCs). Pre-μDCs express the gut trafficking receptor α4β7 and home preferentially to the intestines. They develop in the bone marrow (BM), can differentiate into CCR9⁺ plasmacytoid DCs as well as conventional DCs (cDCs), but preferentially give rise to CD103⁺ intestinal cDCs. Generation of pre-μDCs in vivo in the BM or in vitro is regulated by RA and RA receptor α (RARα) signaling. The frequency of pre-μDCs is reduced in vitamin A-deficient animals and in animals treated with RAR inhibitors. The results define a novel vitamin A-dependent, RA-regulated developmental sequence for DCs and identify a targeted precursor for CD103⁺ cDCs in the gut.

    View details for DOI 10.1038/mi.2012.123

    View details for PubMedID 23235743

    View details for PubMedCentralID PMC3612556

  • In vivo T cell activation induces the formation of CD209(+) PDL-2(+) dendritic cells. PloS one Davidson, M. G., Alonso, M. N., Kenkel, J. A., Suhoski, M. M., González, J. C., Yuan, R., Engleman, E. G. 2013; 8 (10)


    Two critical functions of dendritic cells (DC) are to activate and functionally polarize T cells. Activated T cells can, in turn, influence DC maturation, although their effect on de novo DC development is poorly understood. Here we report that activation of T cells in mice, with either an anti-CD3 antibody or super antigen, drives the rapid formation of CD209(+)CD11b(+)CD11c(+) MHC II(+) DC from monocytic precursors (Mo-DC). GM-CSF is produced by T cells following activation, but surprisingly, it is not required for the formation of CD209(+) Mo-DC. CD40L, however, is critical for the full induction of Mo-DC following T cell activation. T cell induced CD209(+) Mo-DC are comparable to conventional CD209(-) DC in their ability to stimulate T cell proliferation. However, in contrast to conventional CD209(-) DC, CD209(+) Mo-DC fail to effectively polarize T cells, as indicated by a paucity of T cell cytokine production. The inability of CD209(+) Mo-DC to polarize T cells is partly explained by increased expression of PDL-2, since blockade of this molecule restores some polarizing capacity to the Mo-DC. These findings expand the range of signals capable of driving Mo-DC differentiation in vivo beyond exogenous microbial factors to include endogenous factors produced following T cell activation.

    View details for DOI 10.1371/journal.pone.0076258

    View details for PubMedID 24098455

    View details for PubMedCentralID PMC3788745

  • Caspase-8 isoform 6 promotes death effector filament formation independent of microtubules APOPTOSIS Yuan, R. T., Young, S., Liang, J., Schmid, M. C., Mielgo, A., Stupack, D. G. 2012; 17 (3): 229-235


    Caspase-8 can trigger cell death following prodomain-mediated recruitment to the 'death-inducing signaling complex.' The prodomain consists of two death effector domain (DED) motifs that undergo homotypic interactions within the cell. Aside from mediating recruitment of procaspase-8, the prodomains have also been implicated in regulating cell survival, proliferation, death, senescence, differentiation, and substrate attachment. Here, we perform the initial characterization of a novel isoform of caspase-8, designated caspase-8 isoform 6 (Casp-8.6), which encodes both prodomain DEDs followed by a unique C-terminal tail. Casp-8.6 is detected in cells of the hematopoietic compartment as well as several other tissues. When Casp-8.6 expression is reconstituted in caspase-8-deficient cells, Casp-8.6 does not significantly impact cellular proliferation, contrasting with our previous results using a domain-defined 'DED-only' construct that lacks the C-terminal tail. Like the DED-only construct, Casp-8.6 also robustly forms 'death effector' filaments, but in contrast to the DED construct, it does not exhibit a dependence upon intact microtubules to scaffold filament formation. Both types of death effector filaments promote apoptosis when expressed in the presence of full length caspase-8 (isoform 1). Together, the results implicate Casp-8.6 as a new physiological modulator of apoptosis.

    View details for DOI 10.1007/s10495-011-0677-y

    View details for Web of Science ID 000301542100002

    View details for PubMedID 22160860