Project Details
Projekt
Mechanisms of T-cell homeostasis and its perturbation in lymphomagenesis
Applicant
Dr. Jörg Kirberg
Subject Area
Immunology
Hematology, Oncology
Rheumatology
Hematology, Oncology
Rheumatology
Term
from 2013 to 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 225165194
Mature lymphocytes persist over long periods of time while recirculating through the peripheral lymphoid organs. For T-cells, regular contact of the T-cell receptor (TCR) to restricting self-MHC molecules is essential for survival and may trigger homeostatic proliferation upon lymphopenia. Since TCRs vary with respect to affinities for their MHC-ligand and since T-cell homeostasis is also ruled by competition in trans, it is so far unclear how a broad TCR repertoire is actually maintained. In the first funding period we could show that different TCRs can escape interclonal competition since the relevant self-peptide/MHC ligand essential for homeostatic proliferation is stratified by location, probably because the peptide ligand is derived from tissue-specific self-antigens. These results shall be extended using non-TCR transgenic model systems to demonstrate the wider applicability of these findings. We thus aim to clarify the processes behind the homeostasis of T-cells, apparently balancing the competition among T-cells bearing TCRs of varying affinity. Furthermore, the impact of these processes in the development of mature T-cell lymphoma (MTCL) will be addressed, using oncogene transgenic mice (collaboration with RP5) and/or retroviral transduction (RP2). Our findings appears relevant for T-cell lymphoma since previous work by CONTROL-T coworkers (RP2) showed that the time to MTCL outgrowth was much shorter in an oligoclonal TCR situation, implicating homeostatic processes in the pathogenesis of this disease. Elucidating these processes will improve our understanding of T-cell population dynamics and may give additional handles to improve MTCL treatment.
DFG Programme
Research Units
