Altman Lab

Altman Lab

"A great sense of fascination and intellectual curiosity about the mysteries of living organisms was instilled in me early on by an outstanding and very enthusiastic high school biology teacher. To a large extent, I attribute my career choice of basic scientific research to her." — Amnon Altman, Ph.D. // Director, Scientific Affairs
Scientific Affairs, Division of Cellular Biology

Overview

Amnon Altman, Ph.D., and his team study T lymphocytes – white blood cells formed in the thymus that are essential in the body’s fight against infection and disease. In particular, they study the biochemical changes that occur in T lymphocytes when an antigen (a substance that can cause an immune response) activates a binding site on the surface of the T cell, called the T Cell Antigen Receptor (TCR).

T cells mediate important functions in the immune system and are responsible for major types of immune defense responses against bacteria and viruses and against cancer. Because of the central importance to immunity that T cells play, aberrations in their activation process can prevent the immune system from being effective, or can lead to immunological diseases. For example, T cells that react in an abnormally strong manner or expand to exceedingly large numbers can cause undesired effects in the form of autoimmune diseases and harmful inflammation.

Dr. Altman and his laboratory have already identified several proteins critical to the proper activation of T cells. Notable among these is an enzyme called protein kinase C theta (PKCθ), which is essential for T cell activation and survival. Understanding this protein, and others like it, will help in the development of immune therapies, new treatments for autoimmune diseases, and increase the chances for long-term survival of organ transplants. More recent work in the lab resulted in the discovery of a novel activation pathway that operates in regulatory T cells, a T cell subset whose primary role is to prevent excessive immune responses that carry the risk of autoimmunity and inflammation. However, the same regulatory T cells can also have the undesired effect of inhibiting immune responses against growing cancers. Rational manipulation of this pathway could result in enhanced tumor immunity, thereby facilitating the killing of tumor cells by the immune system.

Altman Lab

Publications

JCI Insight

Requirement of Treg-intrinsic CTLA4/PKCη signaling pathway for suppressing tumor immunity

2017-12
Pedros C, Canonigo-Balancio AJ, Kong KF, Altman A
Front Immunol

Phosphoproteomics reveals regulatory T cell-mediated DEF6 dephosphorylation that affects cytokine expression in human conventional T cells

2017-09
Joshi RN, Binai NA, Marabita F, Sui Z, Altman A, Heck AJR, Tegnér J, Schmidt A
Proc Natl Acad Sci USA

NFKB-Pim-1-Eomesodermin axis is critical for maintaining CD8 T-cell memory qualityNFKB-Pim-1-Eomesodermin axis is critical for maintaining CD8 T-cell memory qualityNFKB-Pim-1-Eomesodermin axis is critical for maintaining CD8 T-cell memory qualityNFKB-Pim-1-Eomesodermin axis is critical for maintaining CD8 T-cell memory qualityNFKB-Pim-1-Eomesodermin axis is critical for maintaining CD8 T-cell memory qualityNFKB-Pim-1-Eomesodermin axis is critical for maintaining CD8 T-cell memory quality

2017-02
Knudson KM, Pritzi CJ, Sacena V, Altman A, Daniels MA, Teixeiro E
Proc Natnl Acad Sci USA

NFKB-Pim-1-Eomesodermin axis is critical for maintaining CD8 T-cell memory quality

2017-02
Knudson KM, Pritzi CJ, Sacena V, Altman A, Daniels MA, Teixeiro E
Int J Inflam

Identification of a novel alternatively spliced form of inflammatory regulator SWAP-70-like adapter of T cells

2017-01
Hashimoto M, Nagao JI, Ikezaki S, Tasaki S, Arita-Morioka KI, Narita Y, Cho T, Yuasa K, Altman A, Tanaka Y 
Sci Signal

Chemical proteomic map of dimethyl fumarate-sensitive cyteines in primary human T cells

2016-09
Blewett MM, Xie J, Zaro BW, Backus KM, Altman A, Teijaro JR, Cravatt BF
Nat Immunol

A TRAF-like motif of the inducible costimulator ICOS controls development of germinal center TFH cells via the kinase TBK1

2016-07
Pedros C, Zhang Y, Hu JK, Choi YS, Canonigo-Balancio AJ, Yates JR 3rd, Altman A, Crotty S, Kong KF
Annu Rev Immunol

Protein kinase C enzymes in the hematopoietic and immune systems

2016-05
Altman A, Kong KF
Journal of Cell Science

SLAT promotes TCR-mediated, Rap1-dependent LFA-1 activation and adhesion through interaction of its PH domain with Rap1

2015-12
Côte M, Fos C, Canonigo-Balancio AJ, Ley K, Bécart S, Altman A
Nature Immunology

TCR-induced sumoylation of the kinase PKC-Θ controls T cell synapse organization and T cell activation

2015-11
Wang XD, Gong Y, Chen ZL, Gong BN, Xie JJ, Zhong CQ, Wang QL, Diao LH, Xu A, Han J, Altman A, Li Y
Science Signaling

Association of the EF-hand and PH domains of the guanine nucleotide exchange factor PLAT with IP3 receptor 1 promotes Ca2+ signaling in T cells

2014-09
Fos C, Becart S, Balancio AJ, Boehning D, Altman A
Drug Discovery Today

Protein kinase C inhibitors for immune disorders

2014-08
Altman A, Kong KF
Nature Immunology

Protein C-η controls CTLA-4-mediated regulatory T cell function

2014-05
Kong KF, Fu G, Zhang Y, Yokosuka T, Casas J, Canonigo-Balancio AJ, Becart S, Kim G, Yates JR 3rd, Kronenberg M, Saito…
Advances in Pharmacology

The yin and yang of protein kinase C-theya (PKCΘ): a novel drug target for selective immunosuppression

2014-01
Zhang EY, Kong KF, Altman A
Frontiers in Immunology

Regulation of immune system cell functions by protein kinase C

2013-11
Isakov N, Altman A
Trends in Immunology

In and out of the bull's eye: protein kinase Cs in the immunological synapse

2013-05
Kong KF, Altman A
Journal of Immunology

TNFR-associated factor 6 regulates TCR signaling via interaction with and modification of LAT adapter

2013-04
Xie JJ, Liang JQ, Diao LH, Altman A, Li Y
Journal of Immunology

SLAT regulates CD8+ T cell clonal expansion in a Cdc42- and NFAT1-dependent manner

2013-01
Feau S, Schoenberger SP, Altman A, Bécart S
Frontiers in Immunology

PKC-theta-mediated signal delivery from the TCR/CD28 surface receptors

2012-08
Isakov N, Altman A
Journal of Biological Chemistry

Protein kinace CΘ C2 domainis a phosphotyrosine binding module that plays a key role in its activation

2012-08
Stahelin RV, Kong KF, Raha S, Tian W, Melowic HR, Ward KE, Murray D, Altman A, Cho W
Molecular Vision

SLAT/Def6 plays a critical role in the pathogenic process of experimental autoimmune uveitis (EAU)

2012-07
Vistica BP, Shi P, Nugent L, Tan C, Altman A, Gery I
Expert Review of Clinical Immunology

PKCQ: a new target for selective immunosuppression

2012-03
Altman A, Kong KF
Nature Immunology

A motif in the V3 domain of the kinase PKC-θ determines its localization in the immunological synapse and functions in T cells via association with CD28

2011-10
Kong KF, Yokosuka T, Canonigo-Balancio AJ, Isakov N, Saito T, Altman A
Science Signaling

Itk controls the spatiotemporal organization of T cell activation

2011-10
Singleton KL, Gosh M, Dandekar RD, Au-Yeung BB, Ksionda O, Tybulewicz VL, Altman A, Fowell DJ, Wülfing C
Nature Immunology

To kill, you have to duck an HDAC

2011-04
Altman A, Kong KF
Proceedings of the National Academy of Sciences of the United States of America

Antigen-independent signalosome of CARMA1, PKC(theta), and TNF receptor-associated factor 2 (TRAF2) determines NF-{kappa}B signaling in T cells

2011-02
So T, Soroosh P, Eun SY, Altman A, Croft M
Advances in Immunology

Dynamic palmitoylation and the role of DHHC proteins in T cell activation and anergy

2011-01
Ladygina N, Martin BR, Altman A

Principal Investigator

Amnon Altman, Ph.D.

Director, Scientific Affairs

Dr. Altman has been a Member and Head of the Division of Cell Biology at La Jolla Institute for Immunology since 1990, and now serves as Director of Scientific Affairs. His work focuses on understanding biochemical changes that occur in T lymphocytes once they have been engaged by an antigen. Aberrations in T cell activation can lead to immunological diseases, so understanding how these cells are activated is a fundamental part of understanding how to alter T cell responses in favor of the host.

Dr. Altman received his B.Sc and M.Sc from the University of Tel Aviv, in Israel and his Ph.D. in 1975 from the Weizmann Institute in Rehovot, Israel. Between 1975-78, Dr. Altman received his postdoctoral training at the National Institutes of Health and later at the Scripps Clinic and Research Foundation (SCRF). By 1978, he had been appointed to an Assistant Member position in the Departments of Cellular and Developmental Immunology, Molecular Immunology and Immunology at SCRF. From 1984 to 1990, Dr. Altman served as an Associate Member in the Department of Immunology at SCRF.

Dr. Altman is a member of several editorial boards and research associations as well as the recipient of such awards as the Leukemia Society of America, Inc., Scholarship Award and the American Cancer Society’s Junior Faculty Research Award in 1979.

Lab Members

Ann Balancio

Research Technician IV, Lab Manager

Biosketch:
I graduated from James Madison University with a B.S. in Biology. In 2002, I moved to San Diego. I began working as a Research Technician at the La Jolla Institute of Molecular Medicine under the direction of Dr. Mario Bourdon. Then, in 2003, I joined the Dr. Amnon Altman’s Cell Biology at the La Jolla Institute for Immunology. I have worked on many projects that study t-cell specific signaling and proteins like SLAT and the PKC enzyme family

Hsin-Yu Liu

Postdoctoral Fellow

Biosketch:
In 2014, I received my PhD in Life Science from National Defense Medical Center, Taiwan. Then I worked as a postdoc in the Institute of Molecular Biology, Academia Sinica, Taiwan for two years. Before joining Amnon’s lab at LJI, I studied innate immunity and neurodevelopment focusing on the immunopathology of autism and Alzheimer's disease.

Research Focus:
After I joined the big family of LJI, I am going to investigate the regulatory mechanism of PKC-eta in the Treg-mediated suppression of tumor immunity and hope to provide a target for cancer immunotherapy.

Career Goal:
I hope that my work can contribute to the fields in both academia and industry. Outside of lab, I like painting, hiking, yoga and eating tasty food.

Noa Macdonald

Student Intern

Christophe Pedros

Postdoctoral Fellow

I obtained my Ph.D. in Immunology in 2013 at Paul Sabatier University, Toulouse, France. I was interested in how proximal TCR signaling proteins control regulatory and effector CD4 T cell functions and affect the immune system homeostasis. I began working as a postdoc in Dr. Altman laboratory at the La Jolla Institute for Immunology in January 2014 where I focused on co-stimulatory/inhibitory molecules signaling and their impact on T cell functions. I am now particularly interested in identifying new targets for cancer immunotherapy.

Jiji Xie, Ph.D.

Postdoctoral Fellow

Biosketch:
I obtained both of my B.S degree in Biotechnology in 2007 and Ph.D. in Biochemistry& Molecular Biology in 2012 from Sun Yat-sen University, Guangzhou, China. I have been working as a postdoc in Altman Lab at La Jolla Institute since early 2013.

Research focus:
My research is focused on the roles of Protein Kinase Cs (PKCs) in T cell signaling and function. I am interested in investigating how PKCs integrate and transfer inter-/intra-cellular signals in healthy and pathological scenarios (e.g. cancer), and in developing PKCs as novel therapeutic targets in immune diseases.

Career Goals:

To promote the bench research to the bedside.

Altman Lab

Research Projects

Our research focuses on the molecular basis of signal transduction cascades initiated following triggering of the antigen-specific T cell receptor (TCR)/CD3 complex and costimulatory receptors. T cells play important effector and regulatory functions in the immune system, and aberrations in their activation can lead to immunological diseases. Therefore, understanding of the biochemical events occurring during T cell activation is important in order to rationally devise pharmacological and other treatments designed to modulate the T cell response in favor of the host. Signaling cascades in T cells involve enzymes as well as adaptor proteins that mediate protein-protein interactions essential for the formation of multi-subunit signaling complexes. Some of these signaling elements are specifically expressed in T cells or in hematopoietic cells in general and, thus, constitute potential tissue-selective drug development targets. We have focused our research efforts on several hematopoietic (or T cell)-specific signaling proteins, including PKCq, SLAT and LAT.

PKCq

PKC enzymes play critical roles in the differentiation and proliferation of many cell types, including T cells, and in the response to diverse stimuli. Little is known, however, about the substrate specificity and role of individual PKC isoforms in distinct activation and developmental events in T cells. In 1993, we cloned and identified a novel PKC isoform, PKCq. It is characterized by a unique tissue distribution, i.e., in skeletal muscle, lymphoid organs, and hematopoietic cell lines, in particular T cells. PKCq plays an important role in T cell activation: It selectively activates the transcription factors AP-1 and NF-kB, and integrates TCR and CD28 signals, which lead to activation of the CD28 response element (RE) in the interleukin-2 (IL-2) gene promoter. PKCq also localizes to the center of the T cell immunological synapse (IS) that forms at the contact area between antigen-specific T cells and antigen-presenting cells, and serves as a platform for the transduction of activation signals. Consistent with its important role in T cell activation, mature T cells from PKCq-deficient mice display severely reduced proliferation and IL-2 production, along with impaired activation of NF-kB, AP-1 and NFAT. However, the role of PKCq in T cells is selective since it is required for allergic response mediated by T helper 2 (Th2) cells and autoimmune diseases mediated by Th17 cells, but is largely dispensable for anti-viral immunity. As a result of this selectivity, as well as its relatively specific T cell expression, PKCq has become an attractive drug target.

Other studies on PKCq have recently resolved some enigmas that have dominated the field for a long time, namely, what is the molecular basis for the selective recruitment of this enzyme to the center of the T cell IS, and is this localization essential for the ability of PKCq to activate T cells. Indeed, we found that PKCq‘s unique localization results from its physical association with CD28, a major T cell costimulatory receptor and, furthermore, that a PKCq mutant that does not associate with CD28 fails to activate T cells. These findings form a rational basis for the design of molecular entities that will block the PKCq-CD28 interaction and, therefore, will potentially have the desired effect of inhibiting allergic responses and autoimmune diseases.

We current continue these studies with particular emphasis on the role of PKCq in regulatory T (Treg) cells and in human T cells.

SLAT, a T cell-specific signaling protein

In 2003, we reported the isolation and initial characterization of a novel signaling protein, termed SWAP-70-Like Adaptor of T cells (SLAT; aka Def6), which is selectively expressed in T cells. Upon antigen stimulation, SLAT selectively localizes to the T cell IS, where it plays a key role in initiating cytoskeletal changes and Ca2+ signaling. As a result, T cells that are genetically deficient for SLAT display a severe defect in TCR-induced activation and differentiation into different Th subsets. Our more recent work has elucidated the mechanistic basis for the indispensable role of SLAT in T cell Ca2+ signaling by revealing that , following TCR triggering, SLAT directly binds to the ER-localized inositol triphosphate receptor (IP3R) and facilitates its Ca2+ ion channel function, which initiates Ca2+ signaling in T cells, the latter being required for productive T cell activation and effector functions.

A novel CTLA4-mediated Treg cell-intrinsic signaling pathway

Recent work by others has provided evidence that, in contrast to conventional T cells, PKCq negatively regulates the suppressive activity of Treg cells. Therefore, we initiated efforts to identify other member(s) of the PKC enzyme family, which might positively regulate Treg cell function. This work resulted in the identification of protein kinase C-eta (PKCh) as being required for contact-dependent Treg cell suppressive activity. Furthermore, Treg cell costimulation via the TCR and CTLA4, a major Treg cell-expressed inhibitory receptor required for most suppression pathways, resulted in a direct association between the CTLA4 intracellular domain and PKCh. As a result, strategies that blocked the CTLA4-PKCh interaction impaired the suppressive activity of Treg cells. Interestingly, PKCh-deficient Treg cells lost their ability to inhibit immune response against growing mouse tumors, but retained their ability to inhibit the development of a model autoimmune disease in mice, i.e., adoptive T cell transfer-mediated colitis. Additionally, we found that PKCh-deficient Treg cells display reduced motility and prolonged arrest on antigen-presenting dendritic cells (DC) in vivo, resulting in defective overall depletion of costimulatory DC ligands, an effect that is consistent with reduced suppressive activity and enhanced tumor immunity. We continue to study the mechanistic aspects of this novel signaling pathway, and the applicability of manipulating it in order to enhance tumor-specific immunity.