Research Report 2010 - MDC

Graduate and undergraduatestudentsUta BaddackSven HartmannSusann WinterMathias KochKristina SchradiKatharina WichnerNedjoua MallemJohannes Neuhaus*Felix Oden*Dennis Stauß*Claudia Krause*Elena Babych*Technical AssistantsAndra EisenmannJenny GrobeKerstin KrügerKatrin RäbelHeike SchwedeThorsten Riepenhausen*Florian Weigend*Susanne Scheu*Jens-Philipp Otto*SecretariatDaniela Keyner*part of the period reportedsynovium of diarthrodial joints leads to irreversiblejoint damage, which results in chronic pain and disability.A characteristic feature for RA is the infiltration ofthe synovial tissue by granulocytes and large numbersof mononuclear cells. Another hallmark is the developmentof self-reactive T and B cells, leading to autoantibodyproduction. We have developed a novel combinedmouse model of collagen- and antigen-induced arthritisshowing specific features of the chronic phase inhuman disease. The model is characterized by a rapidformation of ectopic lymphoid follicles as well as antibodiesdirected against collagen type II and citrullinatedpeptides (CCP). CCP-specific antibodies have a highprognostic value in humans and have so far not beendescribed in mouse models of arthritis. However, theprocesses leading to chronic inflammation and thefunction of complex lymphoid microstructures havenot been characterized so far. In this context, we arecharacterizing the role of cytotoxic T lymphocytes(CTLs) and follicular B helper T (T FH ) cells, which inducethe differentiation of B cells into (auto) antibody-producingplasma cells. The development and organizationof these ectopic structures were severely impaired inCXCR5-deficient mice proving its critical role as a signalingmolecule in lymphoid neo-genesis during chronicinflammatory autoimmune diseases. Our results reinforcethe link between chronic inflammation and thegeneration of tertiary lymphoid tissue at extra-nodalsites, which in turn drives local self-antigen-dependentinteraction of memory/effector B and T lymphocytesresulting in aberrant chronic autoreactive immuneresponses.Functional role of CXCR5 in the pathogenesis ofH. pylori-induced chronic inflammatory gastritisA potential relationship between chronic inflammation,establishment of extranodal tertiary follicles andlymphoma pathogenesis has been inferred from gastricMALT lymphomas in humans. In particular, expressionof CXCL13, the ligand for CXCR5, has been associatedwith the formation of ectopic lymphoid follicles and thedevelopment of MALT-lymphoma in H. pylori-infectedpatients. We have analyzed the role of the homeostaticchemokine receptor CXCR5 in the formation of mucosaltertiary lymphoid tissue after H. pylori infection. CXCR5-deficient mice failed to develop lymphoid aggregates inthe glandular stomach and exhibited lower H. pylorispecificserum IgG responses compared to infectedwild-type mice. Thus, the development of mucosal tertiaryectopic follicles during chronic H. pylori infection isstrongly dependent on the CXCL13/CXCR5 signalingaxis.Transcriptional control of follicular B helper T cell(T FH ) differentiationHumoral immunity relies on B cell differentiation intoantibody-secreting plasma cells. Follicular T helper (T FH )cells, a specialized subset of effector T cells, are indispensablefor the generation of these plasma cells, byproviding B cell help during the germinal center (GC)reaction. T FH cells supply signals for the survival, affinitymaturation, isotype switching and immunoglobulinsecretion of GC B cells and are thus important players inthe generation of long-lived, high-affinity antibodysecretingplasma cells as well as memory B cells. Still,the molecular mechanisms through which naïve CD4 Tcells become T FH cells are largely unknown. The projectaims at the identification of critical checkpoints in thedifferentiation of T FH cells in order to better understandthe development of adaptive immune responses. Largescalegene expression analysis of human and murineT FH cells as well as other CD4 T cell populations revealedunique expression patterns for transcriptional regulatorsand signaling molecules belonging e.g. to the deltanotch signaling pathway. Our data suggests that T FHcells constitute a separate lineage of T helper cells witha discrete developmental program and distinguishableeffector function. As cell specialization is oftenCancer Research 117