Dubey, L. K. | bioRxiv Science

bioRxiv2023

B cell-stromal cell cross talk drives mesenteric lymph node eosinophilia during intestinal helminth infection

Eosinophils are involved in host protection against multicellular organisms including helminths and often participate in regulating long-lasting humoral responses. However, their recruitment to the gut-draining mesenteric lymph node (mLN), where they support the development of the adaptive immune response is still elusive. Here, we demonstrate the mechanism underlying the recruitment of eosinophils to the murine mLN post gastrointestinal helminth infection. We found that mLN eosinophils accumulated at immune interactive sites such as the interfollicular and paracortical regions in an IL-4R-dependent manner and was directly associated with the reduced availability of stromal derived eosinophil chemoattractants. Using multiplex imaging we confirmed that eosinophils associate within a stromal niche containing Lyve1+ lymphatic vessels, ER-TR7+Pdpn+ FRCs, and extrafollicular CD138+ plasma cells. Experiments utilising complete and mixed bone marrow chimeras demonstrated that mice lacking IL-4R expression or LT{beta} expression selectively on B cells had diminished eosinophilia and reduced extrafollicular plasma cell numbers within the mLN. When co-cultured with LT{beta}R activated FRCs, eosinophils gained an active phenotype with enhanced Il1rl1 (ST2) receptor expression. LT{beta}R ligation on FRCs resulted in enhanced IL-33 expression along with enrichment of distinct reactomes. Additionally, deletion of LT{beta}R in FRCs reduced the homing capability of eosinophils to the mLN, confirming the significance of lymphotoxin signalling in granulocyte recruitment. Overall, these results highlight the previously unknown role of B cell-stromal cell crosstalk in driving mLN eosinophilia and their potential role in regulating the quality and magnitude of the humoral immune response generated within the mLN.

immunology↗

bioRxiv2023

The murine meninges acquire lymphoid tissue properties and harbour autoreactive B cells during chronic Trypanosoma brucei infection

The meningeal space is a critical brain structure providing immunosurveillance for the central nervous system, but the impact of infections on the meningeal immune landscape is far from being fully understood. The extracellular protozoan parasite Trypanosoma brucei, which causes Human African Trypanosomiasis (HAT) or sleeping sickness, accumulates in the meningeal spaces, ultimately inducing severe meningitis and resulting in death if left untreated. Thus, sleeping sickness represents an attractive model to study immunological dynamics in the meninges during infection. Here, by combining single cell transcriptomics and mass cytometry by time of flight (CyTOF) with in vivo interventions, we found that chronic T. brucei infection triggers the development of ectopic lymphoid aggregates (ELAs) in the murine meninges. These infection-induced ELAs were defined by the presence of ER-TR7+ fibroblastic reticular cells, CD21/35+ follicular dendritic cells, CXCR5+ PD1+ T follicular helper-like phenotype, GL7+ CD95+ GC-like B cells, and plasmablasts/plasma cells. Furthermore, the B cells found in the infected meninges produced high-affinity autoantibodies able to recognise mouse brain antigens, in a process dependent on LT{beta} signalling. A mid-throughput screening identified several host factors recognised by these autoantibodies, including myelin basic protein (MBP), coinciding with cortical demyelination and brain pathology. In humans, we identified the presence of autoreactive IgG antibodies in the cerebrospinal fluid of second stage HAT patients that recognised human brain lysates and MBP, consistent with our findings in experimental infections. Lastly, we found that the pathological B cell responses we observed in the meninges required the presence of T. brucei in the CNS, as suramin treatment before the onset of the CNS stage prevented the accumulation of GL7+ CD95+ GC-like B cells and brain-specific autoantibody deposition. Taken together, our data provide evidence that the meningeal immune response during chronic T. brucei infection results in the acquisition of lymphoid tissue-like properties, broadening our understanding of meningeal immunity in the context of chronic infections. These findings have wider implications for understanding the mechanisms underlying the formation ELAs during chronic inflammation resulting in autoimmunity in mice and humans, as observed in other autoimmune neurodegenerative disorders, including neuropsychiatric lupus and multiple sclerosis.

immunology↗