Artikel
Differential effects of ICOS and CD28 co-stimulation blockade on T follicular helper cells
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Veröffentlicht: | 12. September 2014 |
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Gliederung
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Background: T follicular helper (TFH) cells play a central role in many autoimmune diseases since they are the T cell subset providing help for B cells and their production of (auto-) antibodies in the germinal center (GC) response. Co-stimulatory molecules regulate the differentiation of various T cell subsets and are therefore an attractive therapeutic target.
Methods: We compared the effects of CD28 (Abatacept) and ICOS co-stimulation blockade on TFH cells in an adoptive transfer mouse model which allows to analyze antigen-specific T and B cells in vivo.
Results: Only CD28 blockade prevented early events of TFH cell differentiation like upregulation of the TFH master transcription factor Bcl-6. In contrast, ICOS had an exclusive role for the maintenance of TFH cells in the late phase of the immune response. Without continuous ICOS co-stimulation TFH cells rapidly lost the typical expression pattern of the homing receptors CXCR5, CCR7, PSGL-1, and S1PR1 which are important for their persistence in the B cell zone. TFH cells migrated back into the T cell zone and lost expression of Bcl-6, thereby reverting to non-TFH effector cells. This ultimately resulted in a complete breakdown of the GC response and drastically reduced levels of antigen-specific immunoglobulins.
Conclusion: Our study shows i) that TFH cells are not a stable phenotype in vivo and ii) that factors regulating the intranodal localization of T cells determine their fate. From a clinical point of view, the treatment of already existing autoreactive TFH cells is much more relevant than prevention of the de novo generation, which makes ICOS a promising target for treatment of autoimmune diseases.