A12

A12 Project movie

A12

Project A12 analyzed the immune responses to chronic viral infections with emphasis on a transcriptional pathway of T cell differentiation that generates hypo-responsive cells that curb pathogen replication with limited tissue damage (commonly called “exhaustion”). An important mechanism regulating tissue inflammation is the conversion of pro-inflammatory extracellular ATP to anti-inflammatory ADO by CD39 and CD73. T cell epitopes for both CD8+ and CD4+ T cells were identified for chronic (HBV/HDV, HIV, HCV) and acute (SARS-CoV-2) viral infections, setting the stage for a more detailed analysis of CD39 and CD73 expression on antigen-specific T cells planned for the 2nd funding period. Analysis of CD39 and CD73 expression on T cells in patients with COVID-19 revealed alterations of CD39 and CD73 expression and identified multifunctional T cells in the acute phase of this disease as CD73-/CD39+. Further, project A12 started to investigate the relation of exhaustion and AN signaling molecules in HCV-specific CD8+ T cells, showing as preliminary results a positive correlation between the expression of both PD-1 and CD39 with transcription factor Thymocyte Selection-Associated High Mobility Group Box (TOX) in these patients.

Moreover, project A12 showed that B cells also display significant changes in their repertoire of AN signaling mediators in the course of acute or chronic viral infections. Expression of CD73 is reduced on B cells during acute COVID-19 and chronic HIV infections, and this has been linked to defective isotype switching and B cell hyperactivation, and inhibition of T cell proliferation. B cells are natural candidates to study AN effects on immune functions since they express high levels of AN-metabolizing ectoenzymes (CD38, CD39, and CD73). In human peripheral blood, they are the only sizable leukocyte population that co-expresses CD39 and CD73 and thus are capable of generating ADO from ATP without relying on enzymatic help from neighboring cells. Indeed, self-reliant ADO signaling has been implicated in some B cell functions such as isotype switching, and maintaining B cell quiescence. It is postulated that naïve B cells maintain a “halo” of ADO that acts on A3 receptors in an autocrine fashion and prevents the upregulation of activation markers. Furthermore, B cells release ATP upon receptor-mediated antigen uptake. These observations raise the question of whether this influences their capacity to process and present antigens.

Prof. Dr. Friedrich Haag

Selected publications (*equal contribution)

 

  1. Wildner NH, Ahmadi P, Schulte S, Brauneck F, Kohsar M, Lütgehetmann M, Beisel C, Addo MM, Haag F, Schulze Zur Wiesch J (2021) B cell analysis in SARS-CoV-2 versus malaria: Increased frequencies of plasmablasts and atypical memory B cells in COVID-19. J Leukoc Biol 109: 77-90.
  2. Libera J, Wittner M, Kantowski M, Woost R, Eberhard JM, de Heer J, Reher D, Huber S, Haag F, Schulze Zur Wiesch J. (2020) Decreased Frequency of Intestinal CD39(+) γδ(+) T Cells With Tissue-Resident Memory Phenotype in Inflammatory Bowel Disease. Front Immunol 11: 567472.
  3. Ahmadi P, Hartjen P, Kohsar M, Kummer S, Schmiedel S, Bockmann JH, Fathi A, Huber S, Haag F, Schulze Zur Wiesch J. Defining the CD39/CD73 Axis in SARS-CoV-2 Infection: The CD73(-) Phenotype Identifies Polyfunctional Cytotoxic Lymphocytes. Cells 9(8):1750
  4. Johnsen B, Kaschubowski KE, Nader S, Schneider E, Nicola JA, Fliegert R, Wolf IMA, Guse AH, Nikolaev VO, Koch-Nolte F, Haag F (2019) P2X7-mediated ATP secretion is accompanied by depletion of cytosolic ATP. Purinergic Signal 15: 155-166.
  5. Danquah W, Meyer-Schwesinger C, Rissiek B, Pinto C, Serracant-Prat A, Amadi M, Iacenda D, Knop JH, Hammel A, Bergmann P, Schwarz N, Assunção J, Rotthier W, Haag F, Tolosa E, Bannas P, Boué-Grabot E, Magnus T, Laeremans T, Stortelers C, Koch-Nolte F (2016) Nanobodies that block gating of the P2X7 ion channel ameliorate inflammation. Sci Transl Med 8: 366ra162.
  6. Haag F, Buck F (2015) Identification and analysis of ADP-ribosylated proteins. Curr Top Microbiol Immunol 384: 33-50.
  7. Hubert S, Rissiek B, Klages K, Huehn J, Sparwasser T, Haag F, Koch-Nolte F, Boyer O, Seman M, Adriouch S (2010) Extracellular NAD+ shapes the Foxp3+ regulatory T cell compartment through the ART2-P2X7 pathway. J Exp Med 207: 2561-2568.
  8. Seman M, Adriouch S, Scheuplein F, Krebs C, Freese D, Glowacki G, Deterre P, Haag F, and Koch-Nolte F (2003). NAD-induced T cell death: ADP-ribosylation of cell surface proteins by ART2 activates the cytolytic P2X7 purinoceptor. Immunity 19: 571-582.
  9. Adriouch S, Dox C, Welge V, Seman M, Koch-Nolte F, Haag F (2002) Cutting edge: a natural P451L mutation in the cytoplasmic domain impairs the function of the mouse P2X7 receptor. J Immunol 169: 4108-4112.

PD Dr. Julian Schulze zur Wiesch

Selected publications (*equal contribution)

 

  1. Zhao Y, Kilian C, Turner JE, Bosurgi L, Roedl K, Bartsch P, Gnirck AC, Cortesi F, Schultheiß C, Hellmig M, Enk LUB, Hausmann F, Borchers A, Wong MN, Paust HJ, Siracusa F, Scheibel N, Herrmann M, Rosati E, Bacher P, Kylies D, Jarczak D, Lütgehetmann M, Pfefferle S, Steurer S, Schulze zur Wiesch J, Puelles VG, Sperhake JP, Addo MM, Lohse AW, Binder M, Huber S, Huber TB, Kluge S, Bonn S, Panzer U, Gagliani N, Krebs CF (2021) Clonal expansion and activation of tissue-resident memory-like Th17 cells expressing GM-CSF in the lungs of severe COVID-19 patients. Sci Immunol 6(56):eabf6692.
  2. Heide J., Schulte S., Kohsar M., Brehm T. T., Herrmann M., Karsten H., Marget M., Peine S., Johansson A. M., Sette A., Lütgehetmann M., Kwok W. W., *Sidney J., *Schulze Zur Wiesch J (2021) Broadly directed SARS-CoV-2-specific CD4+ T cell response includes frequently detected peptide specificities within the membrane and nucleoprotein in patients with acute and resolved COVID-19. PLoS Pathog 17(9):e1009842.
  3. Brauneck F., Haag F., Woost R., Wildner N., Tolosa E., Rissiek A., Vohwinkel G., Wellbrock J., Bokemeyer C., Schulze Zur Wiesch J.*, Ackermann C.*, & Fiedler W*(2021) Increased frequency of TIGIT+CD73-CD8+ T cells with a TOX+ TCF-1low profile in patients with newly diagnosed and relapsed AML. Oncoimmunology10(1), 1930391.
  4. Wildner NH, Ahmadi P, Schulte S, Brauneck, F, Kohsar M, Luetgehetmann M, Beisel C, Addo M, Haag F, Schulze zur Wiesch J (2021) B cell analysis in SARS-CoV-2 versus malaria: Increased frequencies of plasmablasts and atypical memory B cells in COVID-19. Journal of Leukocyte Biol 109: 77– 90.
  5. Libera J, Wittner M, Kantowski M, Woost R, Eberhard JM, de Heer J, Reher D, Huber S, Haag F, Schulze Zur Wiesch J (2020) Decreased Frequency of Intestinal CD39+ gd+ T Cells With Tissue-Resident Memory Phenotype in Inflammatory Bowel Disease. Front Immunol 11:567472.
  6. Herrmann M, Schulte S, Wildner NH, Wittner M, Brehm TT, Ramharter M, Woost R, Lohse AW, Jacobs T, Schulze Zur Wiesch J (2020) Analysis of Co-inhibitory Receptor Expression in COVID-19 Infection Compared to Acute Plasmodium falciparum Malaria: LAG-3 and TIM-3 Correlate With T Cell Activation and Course of Disease. Front Immunol 11:1870.
  7. Eberhard JM, Angin M, Passaes C, Salgado M, Monceaux V, Knops E, Kobbe G, Jensen B, Christopeit M, Kröger N, Vandekerckhove L, Badiola J, Bandera A, Raj K, van Lunzen J, Hütter G, Kuball JHE, Martinez-Laperche C, Balsalobre P, Kwon M, Díez-Martín JL, Nijhuis M, Wensing A, Martinez-Picado J, Schulze Zur Wiesch J, Sáez-Cirión A (2020) Vulnerability to reservoir reseeding due to high immune activation after allogeneic hematopoietic stem cell transplantation in individuals with HIV-1. Sci Transl Med 12:eaay9355
  8. Ackermann C, Smits M, Woost R, Eberhard JM, Peine S, Kummer S, Marget M, Kuntzen T, Kwok WW, Lohse AW, Jacobs T, Boettler T, Schulze Zur Wiesch J (2019) HCV-specific CD4+ T cells of patients with acute and chronic HCV infection display high expression of TIGIT and other co-inhibitory molecules. Sci Rep 9(1):10624.
  9. Lindqvist M, van Lunzen J, Soghoian DZ, Kuhl BD, Ranasinghe S, Kranias G, Flanders MD, Cutler S, Yudanin N, Muller MI, Davis I, Farber D, Hartjen P, Haag F, Alter G, Schulze zur Wiesch J, Streeck H (2012) Expansion of HIV-specific T follicular helper cells in chronic HIV infection. J Clin Invest 122:3271-3280.
  10. Schulze zur Wiesch J*, Ciuffreda D *, Lewis-Ximenez L, Kasprowicz V, Nolan B, Streeck H, Aneja J, Reyor L, Allen T, Lohse A, McGovern B, Chung R, Kwok W, Kim A, Lauer G (2012) Broadly directed virus-specific CD4+ T cell responses are primed during acute hepatitis C infection, but rapidly disappear from human blood with viral persistence. J Exp Med 209:6175.

Our Team

Prof. Dr. Friedrich Haag

Insitute of Immunology

University Medical Centre Hamburg-Eppendorf (UKE)

PD Dr. Julian Schulze zur Wiesch

1. Department of Medicine

University Medical Center Hamburg-Eppendorf (UKE)

M.Sc. Klaus Kaschubowski

Insitute of Immunology

University Medical Centre Hamburg-Eppendorf (UKE)

M.Sc. Parimah Ahmadi

1. Department of Medicine

University Medical Center Hamburg-Eppendorf (UKE)

M.Sc. Samantha Wittke

Insitute of Immunology

University Medical Centre Hamburg-Eppendorf (UKE)

M.Sc. Sana Javed

Insitute of Immunology

University Medical Centre Hamburg-Eppendorf (UKE)

Antonia Lehmann

Insitute of Immunology

University Medical Centre Hamburg-Eppendorf (UKE)

Contact

University Medical Center Hamburg-Eppendorf 
Department of Biochemistry and Molecular Cell Biology 
Martinistrasse 52
20246 Hamburg

Scientific Coordinator

Dr. Björn-Philipp Diercks
Fon: +49  (0) 40 7410 54338
E-Mail: b.diercks©uke.de

Administration

Laura Mitsching
Fon: +49  (0) 40 7410 50301
E-Mail: l.mitsching©uke.de