Research group - Annika Karlsson

Our research goal is to define virus-specific T cell immunity in pregnant women, children, adolescents, adults, elderly, and in human cancer with implications for immunopathogenesis, development and regulation of the immune system, and health. We are the link between immune response and health with an empahsize on HIV and SARS-CoV-2 infection.

Research focus

Understanding cellular and molecular dynamics of viral-specific T cell responses

By adapting bioinformatics my group has established a system to evaluate virus-specific CD4 and CD8 T cell responses in genetically diverse populations infected with different viral variants.  The work is based on collecting and identifying T cell responses in well characterized patient cohorts from which we conduct genetic typing of the viral population and the patient’s human leukocyte antigen (HLA) class I and II haplotypes (Figure 1). This, the genetic information of the virus and the host, is essential for our evaluation of HLA – epitope – TCR specific interactions in relation to different aspects of the of pathogen- and malignancy-specific T cell subpopulations in blood and tissue. Our approach has important implications for our potential to identify correlates for the efficacy of virus-specific T cell responses in relation to human health.

Graphic illustraion. T cell activation and memory formation.
Figure 1. T cell activation and memory formation. A) Immunological and virological factors influence generation of virus–specific T cells and may influence the clinical manifestations and quality of the induced T cell response. Here, the ability of the host to generate efficient T cell responses after a viral infection is likely to be dependent on the epitopes targeted, antigen abundance, involvement of resident memory T cells at the site of infection, presence or absence of pre-existing cross-reactive T cells, and host genetic factors such as HLA type and T cell receptor repertoire. B) Viral epitopes (peptides) derived from related virus variants can be presented and cross-recognized by T cells. The level of conservation between related peptide can influence the binding potential to the HLA allele as well as recognition by the T cell receptor. Photo: N/A

Research group leader

Annika Karlsson

Senior Researcher/Biomedical analyst
0704670130

I am a group leader, teacher, Associate Professor and Deputy Head of Division at the Division of Clinical Microbiology, Department of Laboratory Medicine.

My research group is located at ANA Futura, Alfred Nobels Allé 8, KI South, Campus Flemingsberg, in close approximation with the infectious disease clinic and specialist maternity care unit at Karolinska University Hospital Huddinge

I obtained an undergraduate degree in Biomedical Laboratory Science, specializing within the field of clinical microbiology and immunology. Subsequently, I earned an PhD-degree in clinical virology from KI in 2000, followed by 4,5 years as a postdoctoral fellow at Gladstone Institutes of Virology and Immunology, UCSF, San Francisco, broadening my research expertise in clinical immunology, virus-host interactions, especially virus-specific T cell responses and how genetic variability and activity of the virus and host shapes the responding T cell population. I was appointed Associate Professor in clinical virology at Karolinska Institutet in 2009. The research conducted in my group is currently funded by several national grants received from the Swedish Research Council, Centrum for Innovative Medicine, KI Research Foundation Grants, KI Partial funding of new postgraduate student, ALF Med, and The Swedish Physicians Against AIDS Research Foundation.

Group Members

Marion Humbert

Postdoctoral researcher
H7 Department of Medicine, Huddinge

Anna Olofsson

PhD student
H5 Department of Laboratory Medicine

Elin Edlund

ST läkare

Projects

The link between immune response and health in treated HIV-infection

Chronic infection and immunosuppression are important risk factors for many types of cancer. HIV is one chronic infection associated with severe immunosuppression that is only partly reversed by antiretroviral treatment (ART). In an era where HIV-infected individuals require life-long ART to control viral replication it is important to reveal the mechanisms linked to adverse health effects in order to refine therapeutic interventions, especially in pregnant women, children and adolescence. The CD4 and CD8 T cells which is an important part of the adaptive cellular immune system in both cancer and chronic infection becomes highly dysfunctional during an HIV-infection. This process is usually known as T cell exhaustion. In our projects the goal is to gain insights into how to achieve optimized treatment of HIV in perinatally infected children, pregnant women, adults, and in HIV-associated cancers. Thereby leading the way to better clinical outcomes in HIV infected and uninfected patients.

T cell immunity during pregnancy and childhood in relation to viral infection, treatment, and health

ART is necessary during pregnancy and childbirth to prevent HIV mother-to-child transmission (MTCT). Still, 20% of HIV-positive pregnant women in Sweden are not undergoing ART during the first trimester as their HIV status remained unidentified. The combined effect of modern ART and HIV during pregnancy and childhood in relation to T cell immunity, clinical, and obstetrical outcome data, with known effects on morbidity and mortality remains largely unknown (Figure 2). In this collaborative effort between the Karolinska University Hospital, Huddinge, and KI Campus Huddinge we will identify clinical, immunological, and virological factors with implications for health of pregnant women and children (Figure 3). Knowledge acquired through our study can subsequently be used as a standard when evaluating T cell immunity in pregnant women and children in relation to viral infection (i.e., effect on viral pathogenesis), new antiviral treatment strategies, following vaccination, and heath outcome.

Graphic illustration. HIV and T cell immunity
Figure 2. HIV and T cell immunity. HIV infects cells using the CD4 receptor as well as CCR5 or CXCR4 co-receptors. Consequently, one of the first clinical findings indicating an HIV infection is the depletion of CD4 T cells. Though the mechanism behind this depletion is not fully understood, it is likely a combination of viral effects in the cell as well as the chronic inflammation and activation seen in an HIV infection. We cannot cure HIV today as it creates a reservoir in memory CD4 T cells and T follicular helper cells. Another staple of an HIV infection, as well as other chronic infections, is the generation of exhausted T cells. Exhausted HIV-specific T cells express high levels of activation and inhibitory markers in combination with functional impairments preventing them from clearing the infection. A final effect that is relevant for our project is the microbiota dysbiosis associated with progressive HIV infection. Photo: N/A
Graphical illustration. Experimental outline.
Figure 3. Experimental outline. T cell characteristics will be evaluated from multi-colour flow cytometry data acquired using the FACSymphony system. The role of T cell immunity, transcriptional and epigenetic profiling will be investigated in sorted virus-specific T cell populations. To investigate the diversity and dynamic of the microbiome 16s rRNA amplification, sequencing, and metagenomics analysis will be conducted. Multiplex will be used to measure markers associated with immune activation, inflammation, and pharmacokinetics using serological methods established in the main applicant´s group. Bioinformatics approaches, including unsupervised and supervised multidimensional clustering analysis and metagenomics analysis will be conducted. Photo: N/A

The role of cross-reactivity and immune evasion in the control of COVID-19

Our overall goal is to understand the role of SARS-CoV-2-specific CD4 and CD8 memory T cell responses in relation to previous exposure to seasonal human coronaviruses (HCoVs), pathogenic viral SARS-CoV-2 variants, and vaccination (Figure 4). Subsequently, based on the level of viral conservation within a targeted epitope we should be able to predict how effective such immune response, naturally or vaccine induced, would be in targeting specific viral variants.

Graphic illustration. T cell immunity to COVID-19.
Figure 4. T cell immunity to COVID-19. Immunological and virological factors influence generation of SARS-CoV-2–specific T cells and may influence the clinical manifestations and quality of the induced T cell response in acute and convalescent patients with COVID-19 and after vaccination (Karlsson AC, et al, Sci Immunol 2020). Photo: N/A

The role of virus-specific T cell exhaustion in human cancer

HIV is together with human papillomavirus (HPV), Hepatitis B and C viruses (HBV and HCV), and Helicobacter pylori (H. pylori) among the chronic infections related to cancer. In 2012 approximately 195,000 of new cancer cases in Europe were related to chronic infections. Immunosuppression is an important risk factor for many types of cancer. To increase the survival rate in invasive cancer novel immune-based treatment options needs to be developed. To obtain more efficient therapy options for cancer in different stages of development, combinational therapies using immune checkpoints inhibitors to enhance antigen-specific T cell responses are a promising option. Our research goal is to combine clinical, immunological, and molecular biology methodology with bioinformatics to characterize the molecular mechanisms of HIV- and HPV-specific T cells in human cancer affecting disease progression and health (Figure 5). Through the study-outline we will gain mechanistic knowledge of viral- and malignancy-specific T cell exhaustion that can be applied in a variety of cancers where immunomodulation can be used to counteract cancer progression.

Graphic illustration. The stimulatory and inhibitory checkpoint network involving TIGIT.
Figure 5. The stimulatory and inhibitory checkpoint network involving TIGIT. Increasing TIGIT-mediated inhibition of CD8 T-cells parallels downregulation of CD226. TIGIT and CD226 compete in binding to a common receptor, the poliovirus receptor (PVR/CD155). CD226 is a co-stimulatory molecule that is involved in the proliferation and differentiation of T-cells and important for effector functions of CD8 T-cells and NK. Recent data from our group indicates that 2B4 functions as a stimulatory marker together with CD226, but as an inhibitory marker when expressed together with TIGIT and PD-1 (Scharf et. al., ). Photo: N/A

Alumni

PhD students

Main supervisor:

Carina Pérez, 2011

Carina defended her PhD in 2011. Part of her doctoral research was carried out a Gladstone Institutes, University of California, San Francisco together with Prof Douglas Nixon. After her graduation, Carina started up the non-profit company DANSPIRATION in which she through dance aim to inspire, communicate, inform and integrate. Today, Carina is the head of Biosafety at Vironova AB, Stockholm, Sweden.

Melissa Norström, 2012

Melissa defended her PhD in 2012. Part of her doctoral research was carried out at Department of Pathology of the University of Florida College of Medicine together with Prof Marco Salemi. After this she continued as a postdoctoral fellow at Centre for Allogeneic Stem Cell Transplantation (CAST), Department of Oncology and Pathology, KI, Stockholm, Sweden.

Marcus Buggert

Marcus defended his PhD in 2014. He was awarded the Sven Gards stipendium for the best PhD thesis in virologi at KI during 2014. He also received international postdoc grant from the Swedish research council 2014 and joined Dr. Michael Betts lab, Department of Microbiology, University of Pennsylvania, PA, USA. In 2017 he returned to KI, Department of Medicine as an Assistant Professor and became group leader in 2019 https://orcid.org/0000-0003-0633-1719.

Johanna Taurianen, 2016

Johanna defended her PhD in 2016. Since then she has continued her studies on viral-associated CD8 and NK cell responses as a Postdoctoral Fellow in Dr. Jonas Klingström group, Department of Medicine, Center for Infectious Medicine – CIM, Karolinska Institutet.

Lydia Scharf

Lydia defended her PhD in 2020. After graduation Lydia continued her research path as a Postdoctoral Fellow in Group Davide Angeletti, Department of Microbiology and Immunology, University of Gothenburg, Sweden. Lydia is currently investigating B cell responses to COVID19 after infection and vaccination

Co-supervisor:

2013: Karin Sundström, PhD student, MTC, Karolinska Institute, Stockholm.

2012: Charlotte Hedskog, MTC, Karolinska Institute, Stockholm

2010: Annica Lindqvist. PhD student, Karolinska Institute, Stockholm

2009: Andreas Boberg, PhD student, MTC, Karolinska Institute, Stockholm

Licentiate students

Main supervisor:

Leda Parham, 2013

Leda defended her licentiate in 2013. She was part of a SIDA supported collaborative project between Karolinska Institutet and University of Honduras headed by me. Today she is working as a teacher and staff scientist at the Department of microbiology, University of Honduras.

Co-supervisor:

2002: Piotr Nowak. University of Warszawa, Poland, included in the Karolinska Institute Research Training program (KIRT).

Previous postdocs

Marcus Buggert

Emmanuel Tupin

Visiting adress

Annika C Karlsson

Karolinska Institutet, ANA FUTURA,

Division of Clinical Microbiology, Department of Laboratory Medicine

Alfred Nobels Allé 8

141 52 Huddinge

Selected publication

Ancestral SARS-CoV-2-specific T cells cross-recognize the Omicron variant.
Gao Y, Cai C, Grifoni A, Müller TR, Niessl J, Olofsson A, Humbert M, Hansson L, Österborg A, Bergman P, Chen P, Olsson A, Sandberg JK, Weiskopf D, Price DA, Ljunggren HG, Karlsson AC, Sette A, Aleman S, Buggert M
Nat Med 2022 03;28(3):472-476

Identification of resident memory CD8+ T cells with functional specificity for SARS-CoV-2 in unexposed oropharyngeal lymphoid tissue.
Niessl J, Sekine T, Lange J, Konya V, Forkel M, Maric J, Rao A, Mazzurana L, Kokkinou E, Weigel W, Llewellyn-Lacey S, Hodcroft EB, Karlsson AC, Fehrm J, Sundman J, Price DA, Mjösberg J, Friberg D, Buggert M
Sci Immunol 2021 Oct;6(64):eabk0894

Delayed expression of PD1 and TIGIT on HIV-specific CD8 T-cells in untreated HLA-B*57:01 individuals followed from early infection.
Scharf L, Tauriainen J, Buggert M, Hartogensis W, Nolan DJ, Deeks SG, et al
J. Virol. 2020 Apr;():

The known unknowns of T cell immunity to COVID-19.
Karlsson AC, Humbert M, Buggert M
Sci Immunol 2020 Nov;5(53):

Limited immune surveillance in lymphoid tissue by cytolytic CD4+ T cells during health and HIV disease.
Buggert M, Nguyen S, McLane LM, Steblyanko M, Anikeeva N, Paquin-Proulx D, et al
PLoS Pathog. 2018 04;14(4):e1006973

Perturbed CD8+ T cell TIGIT/CD226/PVR axis despite early initiation of antiretroviral treatment in HIV infected individuals.
Tauriainen J, Scharf L, Frederiksen J, Naji A, Ljunggren HG, Sönnerborg A, et al
Sci Rep 2017 01;7():40354

Multidimensional Clusters of CD4+ T Cell Dysfunction Are Primarily Associated with the CD4/CD8 Ratio in Chronic HIV Infection.
Frederiksen J, Buggert M, Noyan K, Nowak P, Sönnerborg A, Lund O, Karlsson AC
PLoS One 2015 ;10(9):e0137635

T-bet and Eomes are differentially linked to the exhausted phenotype of CD8+ T cells in HIV infection.
Buggert M, Tauriainen J, Yamamoto T, Frederiksen J, Ivarsson MA, Michaëlsson J, et al
PLoS Pathog. 2014 Jul;10(7):e1004251

Multiparametric bioinformatics distinguish the CD4/CD8 ratio as a suitable laboratory predictor of combined T cell pathogenesis in HIV infection.
Buggert M, Frederiksen J, Noyan K, Svärd J, Barqasho B, Sönnerborg A, et al
J. Immunol. 2014 Mar;192(5):2099-108