Wielding the double edged sword of T cells in transplantation/transfusion
Molecular mechanisms controlling differentiation, effector function and memory formation of T cells.
Project leader: Derk Amsen
The adaptive immune system constitutes a barrier whenever hematopoietic cells from one individual are transplanted into a genetically non-identical individual. For instance, the presence of small numbers of T cells in a stem cell graft can lead to fatal graft versus host disease. Also, some patients requiring repeated blood transfusions generate antibodies against foreign blood group antigens, making blood transfusion much more difficult or even impossible. The immune system is a double-edged sword, however, and can in fact be exploited to our benefit if we know how to control it. Most notably, transplantation of T cells is increasingly explored as a method to treat certain types of cancer.
T cells are central mediators in the adaptive immune system and the primary culprit in problems associated with transplantation. A thorough understanding of the mechanisms governing these cells is required both for preventing undesired and promoting useful aggression of these cells. In our lab, we study these mechanisms in both CD4 and CD8 T cells, aiming for an understanding from the molecular, to the cellular and the systemic level. As the immune system evolved to protect us from microbial invasion, we try to obtain fundamental insight from microbial infection models and genetically modified mice. On the other hand, we try to incorporate such insights into more translational approaches pertaining to human transplantation therapies.
T helper cells
The immune response is orchestrated by different lineages of CD4+ T helper (Th) cells. Each of these produces its own cocktail of cytokines and thereby mobilizes immune effector mechanisms dedicated to defense against specific classes of microorganisms. The direction of CD4 T cell differentiation is dictated by information from antigen presenting cells (APC), which recognize hallmark features of microbes and instruct the appropriate differentiation program in CD4 T cells. We have shown in the past that the Notch signaling pathway has important roles in this process (Amsen et al., Cell 117, 515; Amsen et al., Immunity 27, 89; Amsen et al., Nature Reviews in Immunology 9, 116). Currently, we study the molecular programs mobilized by Notch to drive these differentiation programs.
A specific class of Th cell, known as follicular T helper cell (TFh), is necessary for the production of high affinity isotype class switched antibodies. TFh cells are characterized by expression of the CXCR5 homing receptor, which allows them to migrate to B cell follicles, where they provide survival signals to B cells undergoing somatic hypermutation and simultaneously instruct antibody class switching. The signals driving differentiation and maintenance of these cells are not known and their identification is another goal of our lab.
A fundamental property of the adaptive immune system consists of the ability to generate long lasting protection against pathogens. This phenomenon, known as immune memory, is critical for the success of vaccinations. We study how the immune system manages to generate an immediately protective response and simultaneously lay the foundation for immune memory. After infection with a virus, two types of CD8 effector T cells are produced: immediately protective, but short lived effector cells (SLECs) as well as memory precursor effector cells (MPECs), which have the capacity to survive long term. Important questions are: which signals determine whether a CD8 T cell develops into a SLEC or into an MPEC? Can these processes be manipulated to selectively promote generation of one or the other? What determines the ability of MPECs to survive? Are there specific signals controlling effector function of memory cells and are these amenable to therapeutic manipulation?
- Helbig C, Amsen D. Notch signaling: piercing a harness of simplicity. Immunity 2015; 43(5):831-3.
- Amsen D, Helbig C, Backer RA. Notch in T cell differentiation: all things considered. Trends in Immunology 2015, 36(12):802-14.
- Backer RA, Helbig C, Gentek R, Kent A, Laidlaw BJ, Dominguez CX, de Souza YS, van Trierum S, van Beek R, Rimmelzwaan GF, ten Brinke A, Willemsen AM, van Kampen AHC, Kaech SM, Magarian Blander J, van Gisbergen K, Amsen D. A central role for Notch in effector CD8+ T cell differentiation. Nature Immunology 2014; 15(12):1143-51.
- Nair-Gupta P, Baccarini A, Tung N, Seyffer F, Florey O, Huang Y, Banerjee M, Overholtzer M, Roche PA, Tampé R, Brown BD, Amsen D, Whiteheart SW, Magarian Blander J. TLR Signals Induce Phagosomal MHC-I Delivery from the Endosomal Recycling Compartment to Allow Crosspresentation. Cell 2014; 158(3):506-21.
- Helbig C, Gentek R, Backer RA, de Souza Y, Derks IA, Eldering E, Wagner K, Jankovic D, Gridley T, Moerland PD, Flavell RA, Amsen D. Notch controls the magnitude of T helper cell responses by promoting cellular longevity. Proc Natl Acad Sci U S A 2012; 109(23):9041-6.
- Sander LE, Davis MJ, Boekschoten MV, Amsen D, Dascher CC, Ryffel B, Swanson JA, Müller M, Blander JM. Detection of prokaryotic mRNA signifies microbial viability and promotes immunity. Nature 2011; 474(7351):385-9.
- Blander JM, Amsen D. Immunology. Amino acid addiction. Science 20095; 324(5932):1282-3.
- Amsen D, Spilianakis CG, Flavell RA. How are T(H)1 and T(H)2 effector cells made? Curr Opin Immunol 2009; 21(2):153-60.
- Amsen D, Antov A, Flavell RA. The different faces of Notch in T-helper-cell differentiation. Nat Rev Immunol 2009; 9(2):116-24.
- Amsen D, Antov A, Jankovic D, Sher A, Radtke F, Souabni A, Busslinger M, McCright B, Gridley T, Flavell RA. Direct regulation of Gata3 expression determines the T helper differentiation potential of Notch. Immunity 2007; 27(1):89-99.
- Amsen D, Blander JM, Lee GR, Tanigaki K, Honjo T, Flavell RA. Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells. Cell 2004; 117(4):515-26.