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Lymphoid tissue returns to a steady state once each immune response is resolved, and although this occurs multiple times throughout life, its structural integrity and functionality remain unaffected. Stromal cells orchestrate cellular interactions within lymphoid tissue, and any changes to the microenvironment can have detrimental outcomes and drive disease. A breakdown in lymphoid tissue homeostasis can lead to a loss of tissue structure and function that can cause aberrant immune responses. This Review highlights recent advances in our understanding of lymphoid tissue function and remodelling in adaptive immunity and in disease states. We discuss the functional role of lymphoid tissue in disease progression and explore the changes to lymphoid tissue structure and function driven by infection, chronic inflammatory conditions and cancer. Understanding the role of lymphoid tissues in immune responses to a wide range of pathologies allows us to take a fuller systemic view of disease progression., Summary: Lymphoid tissue fitness can determine disease severity and affect outcome by altering the course of immune responses. We discuss how lymphoid tissue function can impact disease progression during infections, chronic inflammatory conditions and cancer.

Podoplanin is an inflammatory marker upregulated in many pathologies and correlated with invasive cell behaviour. Podoplanin is reported to facilitate both actomyosin contractility and formation of cell protrusions. However, how podoplanin can elicit these opposing phenotypes is unknown. We examined podoplanin functions in lymph node fibroblastic reticular cells (FRCs), with high endogenous podoplanin expression. We report that podoplanin expression, localisation and function are dependent on partner proteins. CLEC-2 binding up-regulates podoplanin transcription, and tetraspanin CD82 is essential for trafficking of podoplanin to the plasma membrane. At the cell surface, podoplanin regulates cytoskeletal dynamics, balanced by its membrane binding partners hyaluronan receptor CD44 and tetraspanin CD9. Both CD44 and CD9 dampen podoplanin-dependent actomyosin contractility, and in vitro , CD9/podoplanin promotes filopodia-like protrusions whereas CD44/podoplanin promotes lamellipodia formation. Both CD44 and CD9 are required to coordinate protrusion formation and spreading of FRCs in response to CLEC-2 + dendritic cells, a requirement for acute lymph node expansion. In vivo , surface expression levels of podoplanin, CD44 and CD9 are specifically upregulated on T-cell zone FRCs in the early phase of lymph node expansion. Our data support a model whereby podoplanin resides in distinct plasma membrane domains, and that CLEC-2 binding serves as a molecular switch to change podoplanin function.

During viral infection, inflammation and recovery are tightly controlled by competing proinflammatory and regulatory immune pathways. Respiratory syncytial virus (RSV) is the leading global cause of infantile bronchiolitis, which is associated with recurrent wheeze and asthma diagnosis in later life. Th2-driven disease has been well described under some conditions for RSV-infected mice. In the present studies, we used the Foxp3(DTR) mice (which allow specific conditional depletion of Foxp3(+) T cells) to investigate the functional effects of regulatory T cells (Tregs) during A2-strain RSV infection. Infected Treg-depleted mice lost significantly more weight than wild-type mice, indicating enhanced disease. This enhancement was characterized by increased cellularity in the bronchoalveolar lavage (BAL) fluid and notable lung eosinophilia not seen in control mice. This was accompanied by abundant CD4(+) and CD8(+) T cells exhibiting an activated phenotype and induction of interleukin 13 (IL-13)- and GATA3-expressing Th2-type CD4(+) T cells that remained present in the airways even 14 days after infection. Therefore, Treg cells perform vital anti-inflammatory functions during RSV infection, suppressing pathogenic T cell responses and inhibiting lung eosinophilia. These findings provide additional evidence that dysregulation of normal immune responses to viral infection may contribute to severe RSV disease.