J. Claude Bennett Professor of Medicine
Shelby Building, Room 507
1825 University Boulevard
Telephone: (205) 975-3323
BS (Chemistry), University of Denver, Denver, CO, 1987
PhD (Microbiology and Immunology),Duke University, Durham, NC, 1992
Postdoctoral Fellowship, Stanford University, 1992-1996
Research Description and Potential Projects for Trainees
Pulmonary immunity to viruses, tumors and allergens. One of the projects in my lab is to determine how local lymphoid tissues develop and function in the respiratory tract. We find that, although naïve mice lack detectable lymphoid areas in their lungs, organized lymphoid tissues are formed in response to infection or inflammation. These tissues, which we have termed "inducible Bronchus Associated Lymphoid Tissue" (iBALT), have separated B and T cell areas, germinal centers, high endothelial venules and specialized dendritic cells. We also find that immune responses to influenza can be generated at sites of iBALT in mice that completely lack lymph nodes, Peyer’s patches and spleen. In fact, mice lacking conventional lymphoid organs are more resistant to influenza than normal mice. Thus, iBALT is not simply an area of inflammation, but is a site that can actively participate in the immune response and appears to regulate respiratory immune responses in a way that leads to less morbidity and mortality. Consistent with this idea, recent data suggests that humans with non-small cell lung carcinoma who also develop iBALT have a better prognosis than those who not. Thus, we are currently exploring ways to induce iBALT in mouse models of lung cancer to determine whether the purposeful induction of iBALT will lead to cancer regression. On the other hand, we also find that iBALT is generated in the lungs of humans with a wide variety of pulmonary diseases. In particular, humans with lung disease associated with rheumatoid arthritis are very prone to developing extensive areas of iBALT. We suspect that these local lymphoid tissues are responding to autoantigens and exacerbating pulmonary disease. Interestingly, we have also found that there is a developmental window in neonatal mice during which iBALT is most easily formed. This window corresponds to a time when children are at risk of developing asthma in response to respiratory viruses, such as RSV. Thus, iBALT is probably involved in both helpful and harmful immune responses in the lung.
Peritoneal immunity to tumors and commensal organisms. A second project in my lab is to understand the development function of unusual lymphoid tissues in the peritoneal and pleural cavities. These tissues include the milky spots of the omentum and the Fat-Associated Lymphoid Clusters (FALC) in the mesentery. The omentum connects the spleen, stomach, pancreas and colon and is a major depot of abdominal fat, which is a source of inflammatory cytokines and chemokines. In addition, the omentum contains milky spots, which collect fluids, particulates and, importantly, metastasizing tumor cells from the peritoneal cavity. We find that milky spots are functional secondary lymphoid organs. However, we also find that the omentum suppresses immune response to peritoneal tumors. Given that a variety of peritoneal tumors, such as ovarian carcinomas and gastrointestinal stromal cell tumors shed cells that metastasize to the omentum, where they seem to grow unchecked due to a combination of profound immunosuppression and exuberant angiogenesis, it is essential that we understand the mechanisms that allow tumor growth in the omentum in order to treat peritoneal tumor metastases appropriately. Our overall hypothesis is that the normal function of the omentum is to maintain tolerance to commensal organisms and food antigens of the gut. Thus, the omentum has evolved to prime CD4 T cells to become Tregs as well as mucosal-type CD4 T cells that produce IL-10 and TGF and help B cells switch to IgA. However, in the context of tumor antigens, these same functions suppress CD8 T cell responses, promote tolerance to tumor antigens and impair anti-tumor immunity. Thus, my lab is determining the immunological mechanisms by which the omentum suppresses immune response to peritoneal tumors and maintains tolerance to commensal and food antigens.
Control of CD8 T cell responses to viruses and tumors. A third project in my lab is to determine how CD40 signaling controls CD8 T cell responses to viruses and tumors. We find that CD40 signaling is important for both primary and secondary CD8 responses to influenza and tumor antigens. Surprisingly, however, CD4 T cells seem to be dispensable. This scenario is difficult to reconcile with the paradigm that CD40 ligand is expressed by CD4 T cells. Nevertheless, we now have data suggesting that CD4 effector T cells provide CD40 ligand in order to counteract the activities of CD4 Tregs. Thus, in the absence of all CD4 T cells, CD40 ligand is not required. These data suggest that there is a competition between CD4 effectors and Tregs to control the activity of APCs that regulate the priming, expansion and differentiation of CD8 T cells responding to both viruses and tumors. As a first step in testing this hypothesis, we have identified the important APCs (dendritic cell populations) that are required for CD8 T cell responses to influenza and tumor antigens. We are now determining how CD4 effectors and Tregs control the activity/survival/migration of these dendritic cells. Interestingly, different class I restricted epitopes of influenza have different requirements for CD4 cells and CD40 signaling, suggesting that even in a single infection model, each epitope is processed and presented by different cells, which are activated using different pathways. These data will have profound implications on how we vaccinate against specific pathogens and, more importantly, particular epitopes in those pathogens.
Local control of autoimmune/inflamatory T and B cell responses. It is well established that ectopic lymphoid follicles are formed in patients with a variety of autoimmune diseases, including rheumatoid arthiritis, diabetes and multiple sclerosis. These ectopic follicles typically correlate with the most severe forms of disease and are also found at sites of local inflammation or pathology. Thus, most investigators, including us, have concluded that the ectopic follicles are contributing to disease. However, we also find that ectopic follicles promote resistance to infectious disease and reduce inflammation. Therefore, we are trying now to determine the real cause and effect relationship between ectopic follicles and local inflammatory reactions. For example, using mice that have human TNF expressed as a transgene, we showed that these mice develop pulmonary disease, similar to that seen in some RA patients. To test whether the development of ectopic follicles in the lung accelerated disease, we infected the TNF transgenic mice with influenza. Surprisingly, we found that disease was substantially delayed, despite the development of iBALT. Thus, the formation of ectopic follicles may reduce inflammation in autoimmune disease. In another series of experiments, we are using Gaq-/- mice, which spontaneously develop a disease like RA. We are now smoking these mice to determine whether pulmonary exposure to cigarette smoke accelerates disease and/or leads to ectopic follicles in the lung. Finally, we are developing transgenic mice in which we can induce the formation of ectopic follicles in the lungs, brains, pancreas or other organs independently of inflammation. Thus, we can test the ability of ectopic follicles to reduce inflammation in the context of autoimmune disease.
Click here for a more complete list of publications. Below are a few selected papers.
Wiley, JA, LE Richert, SD Swain, A Harmsen, DL Barnard, TD Randall, M Jutila, T Douglas, C Broomell, M Young and AG Harmsen. 2009. Inducible Bronchus-Associated Lymphoid Tissue elicited by a protein cage nanoparticle enhances protection in mice against diverse respiratory viruses. PLOS ONE. 4:e7142 PMC2743193
Ballesteros-Tato, A, B León, FE. Lund and TD. Randall. 2010. Temporal changes in dendritic cell subsets, cross-priming and costimulation via CD70 control CD8+ T cells responses to influenza. Nat. Immunol. 11:216-224. PMC2822886
Randall, TD. 2010. Pulmonary dendritic cells: thinking globally, acting locally. J. Exp. Med. 207:451-454. PMC2839142
Lund, FE and TD Randall. 2010 Regulatory and effector B cells: modulators of CD4+ T cell immunity. Nat. Rev. Immunol. 10:236-247. PMC3038334
Halliley, JL, S Kyu, J Kobie, EE Walsh, AR Falsey, TD Randall, C Feng, I Sanz and FE-H Lee. 2010. Peak frequencies of circulating human influenza-specific antibody secreting cells correlate with protective serum antibodies. Vaccine. 28:3582-3587. PMC2956140
Zhang, S., M Rozell, RK Verma, D Califano, DI Albu, J Van Valkenburgh, A Merchant, J Rangel-Moreno, TD Randall, NA Jenkins, NG Copeland, P Liu and D Avram. 2010. Antigen-specific clonal expansion and cytolytic effector function of CD8+ T lymphocytes depend on the transcription factor Bcl11b. J. Exp. Med. 207:1687-99 PMC2916134
Misra, R.S., Shi, G., Moreno-Garcia, M.E., Thankappan, A., Tighe, M., Kusser, K., Becker-Herman, S., Hudkins Loya, K.L., Dunn, R., Kehry, M.R., Migone, T-S., Marshak-Rothstein, A., Simon, M., Randall, T.D., Alpers, C.E., Liggitt, D. Rawlings, D.J., Lund, F.E. 2010. Gaq-containing G proteins regulate B cell selection and survival and are required to prevent B cell dependent autoimmunity. J. Exp. Med. 207:1775-89 PMC2916136
Cruz A, Fraga AG, Fountain JJ, Rangel-Moreno J, Torrado E, Saraiva M, Pereira DR, Randall TD, Pedrosa J, Cooper AM, Castro AG. 2010. Pathological role of interleukin 17 in mice subjected to repeated BCG vaccination after infection with Mycobacterium tuberculosis. J Exp Med. 207:1609-16. PMC2916141
Chiavolini D, Rangel-Moreno J, Berg G, Christian K, Oliveira-Nascimento L, Weir S, Alroy J, Randall TD, Wetzler LM. 2010. Bronchus-associated lymphoid tissue (BALT) and survival in a vaccine mouse model of tularemia. PLoS One. 5:e11156. PMC2886834
Kaminski DA and TD Randall. 2010. Adaptive immunity and adipose tissue biology. Trends in Immunology. 31:384-390. PMC2949534
Randall TD. 2010. Bronchus-Associated Lymphoid Tissue (BALT): structure and function. Advances in Immunology. 107:183-237.
Kang, DD, Y Lin, J Rangel-Moreno, TD Randall and SA Khader. 2011. Profiling early lung immune responses in the mouse model of tuberculosis. PLOS ONE 6:e1616. PMC3020951
Lee, F. E-H, JL Halliley, EE Walsh, AP Moscatiello, BL Kmush, AR Falsey, TD Randall, DA Kaminski, RK Miller and I Sanz. 2011. Circulating Human Antibody-Secreting Cells during Vaccinations and Respiratory Viral Infections Are Characterized by High Specificity and Lack of Bystander Effect. J. Immunol 186:5514-5521.
LaMere, MW, H-T Lam, A Moquin, L Haynes, FE Lund, TD Randall and DA Kaminski. 2011. Contributions of anti-nucleoprotein IgG to heterosubtypic immunity against influenza virus. J. Virol. 85:5027-5035. PMC3159153
LaMere, MW, A Moquin, FE-H Lee, PJ Blair, L Haynes, TD Randall, FE Lund and DA Kaminski. 2011. Regulation of anti-nucleoprotein IgG by systemic vaccination and its effect on influenza virus clearance. J. Immunol. 186:4331-4339. PMC3126167
Rangel-Moreno, J, DM Carragher, JY Hwang, M de la L Garcia-Hernandez, K Kusser, L Hartson, W Ouyang, J Kolls, SA. Khader and TD Randall. 2011. The development of inducible Bronchus Associated Lymphoid Tissue (iBALT) is dependent on IL-17. Nat Immunol. 12:639-647.
Khader, SA, L Guglani, J Rangel-Moreno, JJ Fountain, C Martino, JE Pearl, Y Lin, S Slight, W Ouyang, JK Kolls, TD Randall and AM Cooper. 2011. IL-23 is required for long-term control of Mycobacterium tuberculosis and B cell follicle formation in the lung. J. Immunol. 187:5402-5407
Ballesteros-Tato and TD Randall. 2011. Memory – the incomplete unhappening of differentiation. Immunity. 35:496-498.
Randall, TD. Stromal cells put the brakes on T cell responses. 2011. Immunology and Cell Biology. 90:469-470.
Rangel-Moreno J, Carragher DM, de la Luz Garcia-Hernandez M, Hwang JY, Kusser K, Hartson L, Kolls JK, Khader SA, Randall TD. 2011. Induction of BALT in the absence of IL-17. Nat Immunol. 13:2
Ballesteros-Tato, A, B León, BA. Graf, A Moquin, PS Adams, FE. Lund and TD Randall. 2012. IL-2 inhibits germinal center formation by limiting T follicular helper responses. Immunity. 36:847-846.
Leon, B, A Ballesteros-Tato, TD Randall and FE Lund. 2012. Parasite-induced TFH and Th2 development relies on B cell dependent positioning of CXCR5+ dendritic cells in the lymph node. Nat Immunol. 13:681-690.
Emo J, Meednu N, Chapman TJ, Rezaee F, Balys M, Randall T, Rangasamy T, Georas SN. 2012 Lpa2 Is a Negative Regulator of Both Dendritic Cell Activation and Murine Models of Allergic Lung Inflammation. J Immunol. 188:3784-3790.
Ballesteros-Tato A, León B, Graf BA, Moquin A, Adams PS, Lund FE, Randall TD. 2012. Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation. Immunity. 36(5):847-56. PMID:22464171 Free PMC Article
León B, Ballesteros-Tato A, Browning JL, Dunn R, Randall TD, Lund FE. 2012. Regulation of T(H)2 development by CXCR5+ dendritic cells and lymphotoxin-expressing B cells. Nat Immunol. 13(7):681-90. PMID:22634865 Free PMC Article
Haynes L, Szaba FM, Eaton SM, Kummer LW, Lanthier PA, Petell AH, Duso DK, Luo D, Lin JS, Lefebvre JS, Randall TD, Johnson LL, Kohlmeier JE, Woodland DL, Smiley ST. 2012. Immunity to the conserved influenza nucleoprotein reduces susceptibility to secondary bacterial infections. J Immunol. 189(10):4921-9. PMID:23028058
Guglani L, Gopal R, Rangel-Moreno J, Junecko BF, Lin Y, Berger T, Mak TW, Alcorn JF, Randall TD, Reinhart TA, Chan YR, Khader SA. 2012. Lipocalin 2 regulates inflammation during pulmonary mycobacterial infections. PLoS One. 7(11):e50052. PMID:23185529 Free PMC Article
Slight SR, Rangel-Moreno J, Gopal R, Lin Y, Fallert Junecko BA, Mehra S, Selman M, Becerril-Villanueva E, Baquera-Heredia J, Pavon L, Kaushal D, Reinhart TA, Randall TD, Khader SA. 2013. CXCR5⁺ T helper cells mediate protective immunity against tuberculosis. J Clin Invest. 123(2):712-26. PMID:23281399 Free PMC Article
Johnston CJ, Manning CM, Rangel-Moreno J, Randall TD, Hernady E, Finkelstein JN, Williams JP. 2013. Neonatal irradiation sensitizes mice to delayed pulmonary challenge. Radiat Res. 179(4):475-84. PMID:23496054
Botelho FM, Rangel-Moreno J, Fritz D, Randall TD, Xing Z, Richards CD. 2013. Pulmonary expression of oncostatin M (OSM) promotes inducible BALT formation independently of IL-6, despite a role for IL-6 in OSM-driven pulmonary inflammation. J Immunol. 191(3):1453-64. PMID:23797667
Ballesteros-Tato A, León B, Lund FE, Randall TD. 2013. CD4+ T helper cells use CD154-CD40 interactions to counteract T reg cell-mediated suppression of CD8+ T cell responses to influenza. J Exp Med. 210(8):1591-601. PMID:23835849
Sedlacek AL, Gerber SA, Randall TD, van Rooijen N, Frelinger JG, Lord EM. 2013. Generation of a dual-functioning antitumor immune response in the peritoneal cavity. Am J Pathol. 183(4):1318-28. PMID:23933065