The nerve growth factor (NGF) receptor (NGFR), also known as p75NTR or CD271, belongs to the tumor necrosis factor (TNF) receptor (TNFR) superfamily. NGFR is a low-affinity pan-receptor of the neurotrophin family of proteins, which includes NGF, the brain-derived neurotrophic factor (BDNF), the neurotrophin-3 (NT3) and the neurotrophin-4/5 (NT4/5) as well as their pre-processed immature forms (known as pro-neurotrophins). Despite being first discovered in the nervous system playing a role in the control of cell survival and apoptosis, NGFR has later been detected in many other organs fulfilling a large variety of functions in different physiological and pathological processes. In this PhD thesis we have analyzed the role of NGFR in secondary lymphoid organs by studying the main alterations in a Ngfr KO mouse model. We found that NGFR absence leads to the development of hypertrophic lymph nodes (LNs) due to spontaneous germinal center (GC) formation and expansion of the B cell compartment. We observed that Ngfr KO mice LNs show alterations in stromal populations with increased frequencies of follicular dendritic cells (FDCs). Detailed characterization by RNAseq and bioinformatic analysis identified an activated phenotype in Ngfr KO FDCs, characterized by the overexpression of CD21/35, MAdCAM-1 and VCAM-1. Moreover, NGFR is down-regulated in FDCs after immunization in wild type mice, concomitant with FDC activation. These data support that NGFR controls both FDCs activation and GC formation in the lymph nodes. Detailed analysis of Ngfr KO LNs showed misplaced location of GCs and loss of polarization between dark zone and light zone. In addition, Ngfr KO mice showed impaired antibody production together with the presence of circulating autoantibodies. However, they do not showed evidence of autoimmune disease. Of note, we found that Ngfr KO/Bcl2 Tg mice showed increased levels of autoantibodies in serum concomitant with a higher incidence of severe autoimmune syndromes such as lupus-like glomerulonephritis, responsible of the decreased overall survival observed in this model. Finally, we found that NGFR levels are reduced in FDCs upon the progression of follicular lymphoma (FL) in the Bcl2 Tg model. Studies in human samples of FL showed reduced NGFR expression early during tumor progression. We are still evaluating the responsible mechanisms involved. Overall, our work identifies NGFR as a crucial molecule maintaining GC structure and functionality in LNs. Our data support that NGFR modulates adaptive immune responses being involved in the regulation of antibody production and immune tolerance

This work was supported by the following fellowships and grants: • La Caixa Foundation fellowship (ID100010434, LCF/BQ/ES17/11600007) • EMBO scientific exchange grant (Number 9156) • RETOS SAF2017-82924-R (AEI/FEDER, UE) • AECC. LABAE19027PEIN. • PDC2021-121102-I00 is funded by MCIN/AEI/10.13039/501100011033 and the European Union “NextGenerationEU”/PRTR

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de Lectura: 02-06-2023

Esta tesis tiene embargado el acceso al texto completo hasta el 02-12-2024