Virtual Memory T cells

New article brings into question how T cell memory should be defined.

New article brings into question how T cell memory should be defined.

We conducted this research to answer a fundamental question in immunology- Where do antigen inexperienced CD4+ T cells reside? 

Currently, it is widely accepted that central and effector memory CD4+ T cells originate from naïve T cells after they have encountered their cognate antigen in the setting of appropriate co-stimulation. However, if this were true the diversity of T cell receptor (TCR) sequences within the naïve T cell compartment should be far greater than that of the memory T cell compartment, which is not supported by TCR sequencing data. In fact the vast majority of T cells with a "memory" phenotype do not appear to have undergone a strong clonal expansion event.

 In our study we demonstrate that aged mice with far fewer naïve T cells, respond to the model antigen, hen eggwhite lysozyme (HEL), by utilizing the same TCR sequence as their younger counterparts. CD4+ T cell repertoire analysis of highly purified T cell populations from HEL-naive animals revealed that the HEL-specific clones, within these mice, displayed effector and central “memory” cell surface phenotypes even though they had never encountered the HEL antigen. Although cross reactivity to some other foreign antigen exposure could have explained these results, the effector and central “memory” HEL-specific T cells that were detected resided at an extremely low frequencies, identical to their frequency within the naive T cell compartment. Thus, any prior cross recognition event was not strong enough to have induced an expansion of the HEL-specific T cells, at least not one that could be detected above the background level that was seen in the naive T cell compartment. In our experiments the HEL-inexperienced CD4+ T cells were found to reside within the naïve, regulatory, central memory, and effector memory T cell populations at similar frequencies.  The vast majority of the other CD4+ T cells within the regulatory and memory populations were also unexpanded.

 These findings support a new paradigm for CD4+ T cell maturation in which a specific clone can undergo a differentiation process to exhibit a “memory” or regulatory phenotype without having undergone a clonal expansion event. They also demonstrate that a foreign-specific T cell is just as likely to reside within the regulatory T cell compartment as it would the naïve compartment, arguing against the specificity of the regulatory T cell compartment being skewed towards self-reactive T cell clones. Finally, we demonstrate that the same set of foreign T cell clones are repetitively generated throughout adulthood.

Trends In NIH Funding

The DEATH of the PHYSICIAN SCIENTIST

In this article published in JAMA Dermatology we demonstrate that MD-only physicians with NIH-funded research programs will become nonexistent in the near future if the current downward trend in federal funding continues. When tracked against PhD and MD/PhD researchers, physicians with ONLY and MD degree are losing funding at a dramatic rate. For more on this topic please see our article in JAMA Dermatology (Click Here-> http://bit.ly/Fundtrend). 

Figure Legend: Graph-> The dollar amount of NIH grants awarded to investigators with MD degrees has decreased significantly (β = −1.35, R2 = 0.81). Meanwhile, the trends for MD/PhD and PhD investigators are not significant (β = 0.25, R2 = 0.15 vs β = −0.24, R2 = 0.03, respectively).

For more interesting trends please see our recent article in JAMA Dermatology-> http://bit.ly/Fundtrend

Guillaume Luxardi, PhD

Experience

Post-Doc Scholar

UC Davis School of Medicine Dept. of Dermatology

January 2014 – Present (3 years 1 month)Institute for Regenerative Cures

The research I am performing is allowing me to acquires expertise in Immunology and Cancer Biology. We are currently designing genetically engineered T Cells and analyzing the phenotypes induced on Melanoma cells

Post-Doc Scholar

UC Davis School of Medicine Dept. of Dermatology

July 2011 – December 2013 (2 years 6 months)Institute for Regenerative Cures

The research I undertake allow me to acquires an interdisciplinary approach combining embryology, genetics, cell and molecular biology with electrophysiology in the context of animal development and regeneration. I am focusing on the integration of bio-physical and bio-chemical cue during tissue repair and regeneration as well as pattern formation during animal development.

ATER (non tenure track Faculty)

Aix-Marseille University

September 2010 – August 2011 (1 year)Developmental Biology Institute of Marseille-Luminy

Lecture and laboratory courses in Cellular biology to Bachelor and Master Students in Biology.

The research I undertook focuses on elucidating the biological functions and integration of BMP, FGF, Nodal and Notch signals during differentiation and morphogenesis in the Xenopus embryo.

Monitor / PhD student

Aix-Marseille University

September 2006 – September 2009 (3 years 1 month)Developmental Biology Institute of Marseille-Luminy

The research I undertook focuses on elucidating the biological functions and integration of BMP, FGF, Nodal and Notch signals during differentiation and morphogenesis in the Xenopus embryo.

Lecture and laboratory courses in Drosophila genetics to Bachelor Students in Biology

Graduate Research Assistant

Aix-Marseille University

June 2005 – September 2005 (4 months)Developmental Biology Institute of Marseille-Luminy

The research I undertook focuses on the establishment of mono layer murine Embryonic Stem Cell (ESC) culture and neural differentiation and on the description of the expression pattern of glypicans genes in mice embryonic and new born brain

Michiko Shimoda, PhD

Position: Assistant Professor, Co-Director Immune Monitoring Shared Resource

PROFILE

Immunologist with over 20 years of experience in broad human and mouse immunology with emphasis in B cell biology and antigen presenting cell functions. Conducted basic and translational research projects in the area of vaccine, autoimmune diseases and cancers with various animal disease models in academic and private institutes.

RESEARCH INTEREST

* Glycans as a tool to modulate immune response

* To identify and characterize natural glycans (human milk glycans and plant glycans) that can modulate antigen-presenting cell function and differentiation.

* To identify key signaling events in immune cells induced by glycans, which are required for glycan-mediated immune modulatory functions.

* To test immune modulatory functions of glycans in animal models of cancers, autoimmune diseases, or in vaccination.

* Immune monitoring of patients with cancers and autoimmune diseases

RESEARCH EXPERIENCE

University of California at Davis, School of Medicine, Department of Dermatology,
Assistant Adjunct Professor

* The anti-inflammatory role of human milk glycans.

* Characterization of anti-inflammatory functions of human milk glycans.

* Identification of key signaling events in human dendritic cells induced by glycans, which are required for glycan-mediated anti-inflammatory functions.

(manuscript in preparation)

* Glycans as a tool for immune therapy

* Identification and characterization of natural glycans (human milk glycans and plant glycans) to modulate myeloid lineage cell function and differentiation.

Medical College of Georgia, School of Medicine,
Assistant Professor

* B cell antigen presentation in immune responses.

* Employed unique B cell restricted MHC-II conditional knockout mice to help understanding the role of B cell antigen presentation in immune response.

Utsunomiya University, Utsunomiya, Japan
Instructor

* Repertoire analysis of mucosal IgA response

* Generated over 20 IgA clones from murine Peyers’ patches using hybridoma technology.

* Characterized mucosal IgA repertoire specificity.

* Understanding the mechanism of memory B cell generation during immune response

* Studied the mechanism of high-affinity B cell selection in germinal centers.

University of Tokyo, Tokyo University of Agricultural and Technology, Tokyo, Japan
PhD

* Understanding the mechanism of high-affinity memory B cell generation for mucosal vaccine development.

* Demonstrated for the first time that high-affinity IgA memory B cells are generated through germinal center response in mucosal associated lymphoid tissues.

INDUSTRY EXPERIENCE

Research Center for Allergy and Immunology, RIKEN, Yokohama, Japan

Research Scientist

Morinaga Milk Industry CO., Tokyo, Japan

Research Scientist

TECHNICAL SKILLS

* Flowcytometry: FACSCanto, FACSFortessa and FACSAriam with multiplex flow cytometry for immune- subset markers with intracellular cytokine staining, phospho- specific flow cytometry.

* Immune-monitoring assays: ELISA assays, ELISPOT and Luminex assays.

* Immune histochemistry.

* Molecular Biology: General molecular biology techniques including PCR, quantitative RT-PCR, cloning and mutagenesis.

* Protein purification: HPLC, gel electrophoresis analysis, Western blotting.

* Antibody production: animal immunization, cell culture, hybridoma generation.

* Animal handling: mouse, rat, guinea pig, and rabbit.

* Animal models: experimental autoimmune encephalomyelitis, colitis, T1 diabetes, skin transplantation, adoptive lymphocyte transfer, bone marrow transfer, xenograft cancers (B16 melanoma, PEL and NHL).

EDUCATION

* Ph.D. Tokyo University of Agriculture and Technology
Tokyo, Japan (2002) Mucosal Immunology

* PhD course University of Tokyo
Tokyo, Japan (1990-1991) Molecular Biology

* MS University of Tokyo, Tokyo, JAPAN
Tokyo, Japan (1984-1986) Agricultural Biochemistry

AWARDS, HONORS AND FELLOWSHIPS

* Research Award (Immunology) by Becton Dickinson to study autoimmune skin diseases.

* Travel Grants from the American Association of Immunologist for attending the annual meetings and International Congress of Immunology

* Travel Grants from the NIAID to attend an annual American Association of Immunologist meeting.

* Presidential Guest Scientist of Tokyo University of Scientist in support with international collaboration on immune regulation.

* Fellowship for young overseas researchers from Japanese government in support with visiting research activity in Dr Garnett Kelsoe’s laboratory, University of Maryland.

GRANTS

* Seed grant Shimoda, M. (PI) 6/01/2016 – 05/31/2017 (UC Davis Dermatology)
“Characterizing sialyl milk oligosaccharides with anti-inflammatory functions” The major goal of this project is to characterize milk oligosaccharides with anti-inflammatory functions using in vitro culture of human dendritic cells.

* PSRP00054 Shimoda, M. (PI) 10/01/2011 – 09/30/2012 (MCG Pilot Study Research Program)
“Regulatory function of IL-10-producing CD8 T cells in immunity and autoimmunity” The major goal of this project was to define the regulatory role of IL-10 producing CD8 T cells in mouse T1 diabetes model.

* NIAID R21 AI064752-01A2 Shimoda, M. (PI) 09/30/2007 – 08/31/2011 (NIH/NIAID)
“Long-lived plasma cell differentiation” The major goal of this project was to define the role of MHC-II-restricted antigen presentation in long-lived plasma cell differentiation of memory B cells.

* NIAMS R03 5R03AR52470-2 Shimoda, M. (PI) 3/01/06-2/28/11 (NIH/NIAMS)
“B cell antigen presentation in models of B cell autoimmunity” The major goal of this project was to understand the role of MHC-II and CD40/CD40L signals in a mouse model of B cell autoimmunity.

* MCGRI grant Shimoda, M. (PI) 10/01/09-09/30/10 (Medical College of Georgia)
“Autonomous CD40 signaling in lymphomagenesis” The aim was to study the role of constitutive CD40 signaling in B malignancy.

* Matuszak Foundation for lupus research Shimoda, M. (PI) 09/01/2008 – 08/30/2009 (Matuszak Foundation, Medical College of Georgia)
“Role of stromal cell surface heat shock proteins in Lupus” The aim was to test the hypothesis that HSP90/DNA complexes displayed on the surface of dying cells trigger B cells to make self-reactive antibodies.

* MCGRI grant Shimoda, M. (PI) 08/01/04-07/31/06 (Medical College of Georgia)
“MHC-II dependent antigen presentation in long-lived plasma cell differentiation” Studies of the role of B cell MHC-II in the differentiation of long-lived plasma cells in bone marrow.

* Grant-In-Aid Shimoda, M. (PI) 04/01/02-03/31/03 (Japanese government)
“Genetic analysis of B cell memory response in LT-beta knock-out mice” The aim was to study follicular dendritc cell (FDC) function B cell memory response generation by analyzing LT-beta knockout mice, which form germinal centers without FDC networks.

NCBI bibliography

Alina Marusina, PhD

Experience 

Assistant Researcher

UC Davis

February 2012 – Present (5 years)

Reserach

Postdoctoral Visiting Fellow

National Institutes of Health

November 2002 – December 2007 (5 years 2 months)

Research

Certifications

MCPS: Microsoft Certified Professional(Link)

Microsoft

Starting April 2012

MCTS: .NET Framework 4, Web Applications(Link)

Microsoft

Starting June 2011

Education

Moscow Institute of Physics and Technology (State University) (MIPT)

Doctor of Philosophy (Ph.D.), Biophysics and Molecular Biology

1997 – 2001

Moscow Institute of Physics and Technology (State University) (MIPT)  Master of Science (MS), Molecular Biology1991 – 1997

Emanual Maverakis, MD

Emanual Maverakis, MD-    Principal Investigator

Dr. Maverakis runs a UC Davis clinic that specializes in the treatment of patients with severe immune-mediated diseases involving the skin and skin cancers such as melanoma and cutaneous T cell lymphoma. He is also an immunology researcher who holds early career awards from the Howard Hughes Medical Institute and the Burroughs Wellcome Fund.

“In order to gain insight into the pathogenesis of autoimmunity the first step is to identify and characterize the T cells involved.”

Dr. Maverakis became interested in immunology as an undergraduate at the University of California-Los Angeles where he earned departmental honors for his work on a mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis. He then continued his research endeavors at Harvard Medical School (HMS) in Boston where he graduated summa cum laude in 2003. He is in a elite group of only 15 students in over 220 years to have graduated with highest honors from HMS. After completing an internship in internal medicine at Harvard’s Beth Israel Deaconess Medical Center, Dr. Maverakis came to UC Davis to complete a residency in dermatology and in 2007 he joined the faculty. He holds appointments in the Department of Dermatology and in the Department of Medical Microbiology and Immunology. 

His lab investigates the pathophysiology of autoimmunity, how T cells (a type of white blood cell) develop and mature, and cancer immunotherapy.  His group is also interest in how foods interact with our immune system; how the immune system recognizes cancer, especially melanoma; developing novel hydrogels, especially with regards to delivering stem cells and immunotherapeutics; clinical trial design, and outcome measures.  Some diseases of special interest include psoriasis, scleroderma, pyoderma gangrenous, pemphigus vulgaris, bullous pemphigoid, melanoma, and cutaneous T cell lymphoma.  

Education

B.S. Microbiology and Molecular Genetics-                 University of California, Los Angeles

M.D. Medicine with special studies in Immunology-                        Harvard Medical School

Honors and Awards

MD Summa Cum Laude, Harvard Medical School | NIH Director's New Innovator Award, National Institutes of Health | Career Award for Medical Scientists, Burroughs Welcome Fund | Physician-Scientist Career Award, Howard Hughes Medical Institute | PECASE, President Barack Obama

Ultraviolet Light

UV radiation: the risks and benefits of a healthy glow

Emanual Maverakis, M.D., University of California, Davis and Andrea Sukhov, University of California, Davis
Eighty years ago, when sun exposure was first associated with skin cancer, popular culture was exalting tanning by emphasizing that a “fine brown color suggests health and good times, and is a pleasant thing to see.”
We know that sun exposure can be deadly, and today’s public awareness campaigns strongly focus on sun avoidance to prevent skin cancer. But we also know that sunlight is important to our health and plays a role in many biological processes in our bodies.
In fact, some physicians and scientists are taking a closer look at sunlight to expose the lesser known benefits of ultraviolet (UV) light.

What is UV light?

When we are talking about the dangerous component of sunlight, we are really talking UV light. UV light is ionizing radiation, meaning that it frees electrons from atoms or molecules, causing chemical reactions. UV light is divided into three categories listed in order of increasing energy: UVA, UVB, UVC.
UVC is the most harmful, but the ozone layer and other components of the atmosphere filter all of it out before it reaches us. That’s also the case for a large percentage of UVB light. But nearly all UVA light reaches the Earth’s surface.
Both latitude and season play large factors in our individual exposure to UV radiation. Countries farthest from the equator during winter months receive the least amount of UV radiation, while equatorial countries receive the most.

UV light causes chemical reactions in the body

Unlike visible light, the energy from UV radiation can be absorbed by molecules in our body, causing chemical reactions. When the energy from UV radiation is absorbed by DNA, it can cause reactions that lead to genetic mutations. Some of these mutations can lead to the development of skin cancer, which is the most common cancer in the U.S. Basal cell carcinoma, squamous cell carcinoma and malignant melanoma (one of the deadliest cancers) are all associated with UV light exposure.

Making some vitamin D. ethermoon/Flickr, CC BY-ND

However, not all chemical reactions that UV light induces are harmful. In fact, some of them are beneficial. For instance, we can get vitamin D from eating certain plants and animals, but a main source of vitamin D comes from exposure to UV radiation.
Vitamin D is critical to maintaining bone density by increasing calcium absorption in the gut. Chronically low levels of vitamin D can lead to osteoporosis. Apart from its effects on bone, vitamin D has also been shown to improve balance and muscle strength in the elderly, which decreases the number of falls leading to fracture.
UV light induces the body to synthesize other molecules as well, including opioid-like molecules thought to cause a tanning “high.”

UV decreases cancer mortality

Research suggests that the risk of developing lung, prostate, breast, colorectal and pancreatic cancer may be decreased by sun exposure. This protective effect against cancer is most pronounced in sunny countries. While smaller studies of colorectal and prostate cancer have conflicted with this finding, many studies support a beneficial relationship between sun exposure and internal cancers, and it has been suggested that the risks associated with sun exposure may be outweighed by its ability to prevent certain types of internal cancers.
Sunlight may also improve cancer outcomes. The prognosis for patients diagnosed in summer and fall is better than those diagnosed in winter, and total sun exposure prior to diagnosis is a predictor of survival.
Given the relationship between sun exposure and vitamin D production, it was initially thought that vitamin D was the underlying cause for improved cancer outcomes. Unfortunately, data to support this are still lacking. Initial trials of vitamin D supplementation have failed to demonstrate a benefit on cancer prevention, which has led researchers to believe that this benefit is from the effects of UV radiation.

UV light decreases blood pressure and inflammation

UV exposure positively affects blood pressure as well. People living in countries in higher latitudes with less UV exposure have higher blood pressures at baseline than countries receiving more sunlight. This effect is also seasonal, as more UV exposure in summer results in lower blood pressure.
And clinical trials have proven UVB radiation effectively treats patients with mild hypertension. It was thought that vitamin D was the cause for decreased blood pressure, but follow-up trials proved this effect was due to UVB exposure alone.
Some chemical reactions caused by UV light are known to have anti-inflammatory effects in the skin. Immune cells living in the skin can stop functioning, migrate out of the skin or undergo cell death following exposure to UV radiation. Due to its anti-inflammatory effects, UV light can be used to effectively treat inflammatory skin conditions like psoriasis and eczema.

Protection against autoimmune conditions

On a larger scale, certain autoimmune conditions are more common in countries with less UV exposure. For instance, there is a higher prevalence of multiple sclerosis (MS) in Scandinavian countries.
In MS, immune cells attack the insulation around nerve cells in the brain, ultimately leading to nerve damage. While lack of vitamin D is a leading hypothesis for how MS develops, studies have also shown that lack of sun exposure may be an independent risk factor for nerve damage.

Be careful out there. Alex Liivet/Flickr, CC BY

Of course, sunlight has a dark side

In addition to skin cancer, UV radiation also causes photoaging. UVA radiation penetrates deep into the skin, destroying collagen, which leads to wrinkles and skin thinning. Also, some autoimmune diseases, such as lupus, flare in response to UV radiation. UV radiation can also affect the eye, causing cataracts.
So, how can you maximize the benefits of sun exposure while minimizing your risk of skin cancer and aging? The key is to practice safe sun habits, which means using sunscreen and avoiding sunburns. This will decrease photoaging, and more importantly, your risk of skin cancer. Also, vitamin D is most effectively synthesized at UV radiation doses below those causing sunburn.
Several factors, including your skin type, latitude, longitude and weather, play into your overall UV exposure. This means different amounts of time in the sun for different people. People living in California may need only brief sun exposure on a cloudless day for adequate vitamin D production. This differs for places like Boston, where there aren’t adequate amounts of UV radiation from November to February. Skin type becomes important because melanin, which gives skin its pigment, effectively blocks UV radiation. This means darker-skinned people need more UV exposure for adequate vitamin D production than lighter-skinned people.
There are online tools that let you calculate how much time you should spend in the sun to achieve adequate levels of vitamin D without causing sunburn. If you think you aren’t getting enough sun exposure, or you live somewhere with long winters, check with your doctor to see if you are vitamin D deficient.

Emanual Maverakis, M.D., Associate Professor- Departments of Medical Microbiology & Immunology and Dermatology | Member- Foods For Health Institute | Member- Comprehensive Cancer Center | Director- Autoimmunity | Director- Immune Monitoring Core, University of California, Davis and Andrea Sukhov, Medical student, University of California, Davis
This article was originally published on The Conversation. Read the original article.