Richard J. Hodes, M.D.
Richard J. Hodes, M.D.
Senior Investigator
Head, Immune Regulation Section
Director, National Institute on Aging

Richard Hodes’ lab studies regulation of the development and function of the adaptive immune system. Ongoing work is focused on the role of T cell receptor and co-stimulatory signals in thymic development and T cell-dependent immune responses, and on the maintenance of chromosomal integrity and proliferative capacity during lymphocyte development and activation.

Areas of Expertise
1) thymus development 2) T cell receptor 3) costimulation 4) tumor suppressor p53 5) ataxia telangiectasia mutated

Contact Info

Richard J. Hodes, M.D.
Center for Cancer Research
National Cancer Institute
Building 10, Room 4B36
Bethesda, MD 20892
301-496-3129
hodesr@31.nia.nih.gov

Cellular and Molecular Regulation of Immune Response

The Role of Costimulatory Receptors in Lymphocyte Activation. A primary area of interest in this laboratory is the study of costimulatory molecules and their function. Costimulation has been extensively studied in the T cell receptor (TCR)-mediated activation of mature T cells. In recent efforts, we have focused on analysis of costimulatory function in T cell development, homeostasis, and effector function. Findings include striking effects of costimulation on critical check-points in thymic development and are using genetic manipulation to elucidate the molecular mechanisms mediating these effects.

We recently identified a critical role of TRAF3 in mediating the requirement for cross-talk between SP thymocytes and thymic epithelial cells (TEC). Using conditional gene inactivation, we found that deleting TRAF3 from TEC completely eliminated the requirement for SP thymocytes in medullary TEC (mTEC) development. The normal function of SP T cells is thus to overcome this TRAF3-dependent inhibition, through multiple signaling pathways capable of TRAF3 inactivation and NFkB alternative pathway activation.

Regulation of Chromosomal Integrity and Lymphocyte Replicative Capacity. This work analyzed the role of telomerase and telomere length regulation. Recent findings included:

  • Telomerase activity is highly regulated during activation and development of T and B lymphocytes, and this regulation is mediated by both transcriptional and posttranslational mechanisms.
  • Telomere length in normal somatic cells is genetically regulated. We have shown that differences in telomere length between mouse species are regulated by a single recessive locus on distal chromosome 2. These findings demonstrated that increases in telomere length can occur during normal differentiation.
  • Telomere length in vivo is regulated by telomerase expression. We have recently shown that telomere length is regulated by expression of telomerase RNA template (TER), and have demonstrated haploinsufficiency in telomere maintanence in heterozgous TER knock-out mice. We generated both knock-out and transgenic models of telomerase reverse transcriptase (TERT) expression to further assess function in vivo.

We have recently extended studies of chromosomal stability and control of lymphocyte proliferation to study two critical components of these regulatory pathways: ATM and tumor suppressor p53.

A recombinase-associated gene (Rag)-dependent mechanism mediates TCR translocation in thymic lymphomagenesis in mice deficient for the ataxia telangiectasia mutated (ATM) gene. ATM plays a role in repair responses to double-strand DNA breaks and influences telomere maintenance. We have characterized the role of ATM in Rag-dependent and Rag-independent recombination in tumorigenesis and have shown a role for ATM in Ig class switch recombination.

We have recently reported that ATM functions to regulate rearrangement of TCR beta and TCR alpha and to regulate the corresponding stages of TCR-dependent thymocyte development. In the absence of ATM, we found a notable instability of RAG-mediated TCR break complexes, with resulting increase of trans rearrangements between TCR loci on different chromosomes. These trans rearrangements result in expression of hybrid TCR chains, which have in turn allowed elucidation of the role of TCR in determining lineage and MHC restriction, two basic attributes of T cell development and function.

We have recently analyzed the role of tumor suppressor p53 in regulating proliferative responses of T cells to antigen-specific and nonspecific signals. These studies led to the striking finding that antigen-specific proliferative responses of na? and memory CD4 T cells require the down-modulation of tumor suppressor p53. In the absence of TCR signal, IL-2 induces a sustained increase in p53 protein, which prevents proliferative responses despite strong signaling through the IL-2 receptor. In contrast, TCR signaling results in early termination of p53 protein expression by decreasing p53 mRNA as well as by strong transcriptional induction of the p53-regulating protein Mdm2. Down-modulation of p53 in response to antigen stimulation is in fact critical for antigen-specific T cell proliferation; and preventing p53 degradation by inhibiting Mdm2 results in sustained p53 protein levels and prevents antigen-specific T cell proliferation. These studies elucidate a critical role of p53 as a negative regulator of T cell proliferation. It is the termination of p53 elevation by TCR signaling that allows proliferative responses to occur, enforcing antigen specificity.

Scientific Focus Areas:
Cell Biology, Immunology

View Dr. Hodes' PubMed Summary.

Selected Key Publications
  1. Watanabe M, Moon KD, Vacchio MS, Hathcock KS, Hodes RJ.
    Immunity. 40: 681-91, 2014. [ Journal Article ]
  2. Jenkinson SR, Williams JA, Jeon H, Zhang J, Nitta T, Ohigashi I, Kruhlak M, Zuklys S, Sharrow S, Adams A, Granger L, Choi Y, Siebenlist U, Bishop GA, Hollander GA, Takahama Y, Hodes RJ.
    Proc. Natl. Acad. Sci. U.S.A. 110: 21107-12, 2013. [ Journal Article ]
  3. Hathcock KS, Laszlo G, Dickler HB, Bradshaw J, Linsley P, Hodes RJ.
    Science. 262: 905-7, 1993. [ Journal Article ]
  4. Hathcock KS, Laszlo G, Pucillo C, Linsley P, Hodes RJ.
    J. Exp. Med. 180: 631-40, 1994. [ Journal Article ]
  5. Weng NP, Levine BL, June CH, Hodes RJ.
    Proc. Natl. Acad. Sci. U.S.A. 92: 11091-4, 1995. [ Journal Article ]

Dr. Hodes received his M.D. from Harvard Medical School and completed a research fellowship at the Karolinska Institute in Stockholm and clinical training in internal medicine at Massachusetts General Hospital before coming to the NIH. He is chief of the Immune Regulation Section of the Experimental Immunology Branch as well as director of the National Institute on Aging.

Name Position
Steven Bowen Postdoctoral Fellow (CRTA)
Yungping (Jeffrey) Chiang, Ph.D. Staff Scientist
Chiharu Fujihara Ph.D. Postdoctoral Fellow (Visiting)
Karen S. Hathcock B.S. Staff Scientist
Hyein Jeon Postbaccalaureate Fellow
Masashi Watanabe Ph.D. Postdoctoral Fellow (Visiting)
Yuri Watanabe Special Volunteer
Joy Williams Ph.D. Senior Research Assistant

Research

Cellular and Molecular Regulation of Immune Response

The Role of Costimulatory Receptors in Lymphocyte Activation. A primary area of interest in this laboratory is the study of costimulatory molecules and their function. Costimulation has been extensively studied in the T cell receptor (TCR)-mediated activation of mature T cells. In recent efforts, we have focused on analysis of costimulatory function in T cell development, homeostasis, and effector function. Findings include striking effects of costimulation on critical check-points in thymic development and are using genetic manipulation to elucidate the molecular mechanisms mediating these effects.

We recently identified a critical role of TRAF3 in mediating the requirement for cross-talk between SP thymocytes and thymic epithelial cells (TEC). Using conditional gene inactivation, we found that deleting TRAF3 from TEC completely eliminated the requirement for SP thymocytes in medullary TEC (mTEC) development. The normal function of SP T cells is thus to overcome this TRAF3-dependent inhibition, through multiple signaling pathways capable of TRAF3 inactivation and NFkB alternative pathway activation.

Regulation of Chromosomal Integrity and Lymphocyte Replicative Capacity. This work analyzed the role of telomerase and telomere length regulation. Recent findings included:

  • Telomerase activity is highly regulated during activation and development of T and B lymphocytes, and this regulation is mediated by both transcriptional and posttranslational mechanisms.
  • Telomere length in normal somatic cells is genetically regulated. We have shown that differences in telomere length between mouse species are regulated by a single recessive locus on distal chromosome 2. These findings demonstrated that increases in telomere length can occur during normal differentiation.
  • Telomere length in vivo is regulated by telomerase expression. We have recently shown that telomere length is regulated by expression of telomerase RNA template (TER), and have demonstrated haploinsufficiency in telomere maintanence in heterozgous TER knock-out mice. We generated both knock-out and transgenic models of telomerase reverse transcriptase (TERT) expression to further assess function in vivo.

We have recently extended studies of chromosomal stability and control of lymphocyte proliferation to study two critical components of these regulatory pathways: ATM and tumor suppressor p53.

A recombinase-associated gene (Rag)-dependent mechanism mediates TCR translocation in thymic lymphomagenesis in mice deficient for the ataxia telangiectasia mutated (ATM) gene. ATM plays a role in repair responses to double-strand DNA breaks and influences telomere maintenance. We have characterized the role of ATM in Rag-dependent and Rag-independent recombination in tumorigenesis and have shown a role for ATM in Ig class switch recombination.

We have recently reported that ATM functions to regulate rearrangement of TCR beta and TCR alpha and to regulate the corresponding stages of TCR-dependent thymocyte development. In the absence of ATM, we found a notable instability of RAG-mediated TCR break complexes, with resulting increase of trans rearrangements between TCR loci on different chromosomes. These trans rearrangements result in expression of hybrid TCR chains, which have in turn allowed elucidation of the role of TCR in determining lineage and MHC restriction, two basic attributes of T cell development and function.

We have recently analyzed the role of tumor suppressor p53 in regulating proliferative responses of T cells to antigen-specific and nonspecific signals. These studies led to the striking finding that antigen-specific proliferative responses of na? and memory CD4 T cells require the down-modulation of tumor suppressor p53. In the absence of TCR signal, IL-2 induces a sustained increase in p53 protein, which prevents proliferative responses despite strong signaling through the IL-2 receptor. In contrast, TCR signaling results in early termination of p53 protein expression by decreasing p53 mRNA as well as by strong transcriptional induction of the p53-regulating protein Mdm2. Down-modulation of p53 in response to antigen stimulation is in fact critical for antigen-specific T cell proliferation; and preventing p53 degradation by inhibiting Mdm2 results in sustained p53 protein levels and prevents antigen-specific T cell proliferation. These studies elucidate a critical role of p53 as a negative regulator of T cell proliferation. It is the termination of p53 elevation by TCR signaling that allows proliferative responses to occur, enforcing antigen specificity.

Scientific Focus Areas:
Cell Biology, Immunology

Publications

View Dr. Hodes' PubMed Summary.

Selected Key Publications
  1. Watanabe M, Moon KD, Vacchio MS, Hathcock KS, Hodes RJ.
    Immunity. 40: 681-91, 2014. [ Journal Article ]
  2. Jenkinson SR, Williams JA, Jeon H, Zhang J, Nitta T, Ohigashi I, Kruhlak M, Zuklys S, Sharrow S, Adams A, Granger L, Choi Y, Siebenlist U, Bishop GA, Hollander GA, Takahama Y, Hodes RJ.
    Proc. Natl. Acad. Sci. U.S.A. 110: 21107-12, 2013. [ Journal Article ]
  3. Hathcock KS, Laszlo G, Dickler HB, Bradshaw J, Linsley P, Hodes RJ.
    Science. 262: 905-7, 1993. [ Journal Article ]
  4. Hathcock KS, Laszlo G, Pucillo C, Linsley P, Hodes RJ.
    J. Exp. Med. 180: 631-40, 1994. [ Journal Article ]
  5. Weng NP, Levine BL, June CH, Hodes RJ.
    Proc. Natl. Acad. Sci. U.S.A. 92: 11091-4, 1995. [ Journal Article ]

Biography

Dr. Hodes received his M.D. from Harvard Medical School and completed a research fellowship at the Karolinska Institute in Stockholm and clinical training in internal medicine at Massachusetts General Hospital before coming to the NIH. He is chief of the Immune Regulation Section of the Experimental Immunology Branch as well as director of the National Institute on Aging.

Team

Name Position
Steven Bowen Postdoctoral Fellow (CRTA)
Yungping (Jeffrey) Chiang, Ph.D. Staff Scientist
Chiharu Fujihara Ph.D. Postdoctoral Fellow (Visiting)
Karen S. Hathcock B.S. Staff Scientist
Hyein Jeon Postbaccalaureate Fellow
Masashi Watanabe Ph.D. Postdoctoral Fellow (Visiting)
Yuri Watanabe Special Volunteer
Joy Williams Ph.D. Senior Research Assistant