Cell Distance Mapping Identifies Functional T Follicular Helper Cells in Inflamed Human Renal Tissue

Abstract

T follicular helper (TFH) cells are critical for B cell activation in germinal centers and are often observed in human inflamed tissue. However, it is difficult to know if they contribute in situ to inflammation. Expressed markers define TFH subsets associated with distinct functions in vitro. However, such markers may not reflect in situ function. The delivery of T cell help to B cells requires direct cognate recognition. We hypothesized that by visualizing and quantifying such interactions we could directly assess TFH cell competency in situ. Therefore, we developed computational tools to quantify spatial relationships between different cell subtypes in tissue (Cell Distance Mapping, CDM). Analysis of inflamed human tissues indicated that measurement of internuclear distances between TFH and B cells could be used to discriminate between cognate and non-cognate interactions. Furthermore, only cognate-competent TFH cell populations expressed high levels of Bcl-6 and IL-21. These data suggest that CDM can be used to identify adaptive immune cell networks driving in situ inflammation. Such knowledge should help identify diseases, and disease subsets, that may benefit from therapeutics targeting of specific T cell:antigen presenting cell interactions.

The immune cell landscape in kidneys of lupus nephritis patients

“…Our transcriptomic analysis also identified multiple CD4 + T cell populations, including a population that expressed features of TFH cells, consistent with prior reports 41,42 . The clustering together of TFH-like cells and FoxP3 + Helios + regulatory T cells further raises the possibility that T follicular regulatory cells are also present 43,44 .…”

Lichenoid Dermatitis in Three Patients with Metastatic Melanoma Treated with Anti–PD-1 Therapy

“…For histologic analyses, anti-CD3 antibody was purchased from Leica Biosystems (Novocastra; ref. 9); anti-CD4 and anti-CD8 antibodies were purchased from Ventana (10); anti-PD-1 antibody was purchased from Abcam (11). All IHC analyses were performed at the Mayo Core Department using standard methods as described in the references.…”

B Cells, Antibodies, and More

“…These are often organized along with T cells and DCs into lymph node-like structures that are known as tertiary lymphoid tissues (151,153,154). B lymphocytes within these structures are actively dividing (supported by local BAFF and APRIL), are undergoing somatic hypermutation, and sometimes form germinal centers (151,(153)(154)(155). The presence of germinal centers is strongly associated with tubular basement membrane immune complexes, providing a highly plausible link between local B-lymphocyte activation and progression of lupus nephritis in humans (151,153,154).…”

“…These are often organized along with T cells and DCs into lymph node-like structures that are known as tertiary lymphoid tissues (151,153,154). B lymphocytes within these structures are actively dividing (supported by local BAFF and APRIL), are undergoing somatic hypermutation, and sometimes form germinal centers (151,(153)(154)(155).…”