Last weekend marked the eightieth anniversary of the Battle of Britain. In 1940, many planes were shot down in flames. Whilst this can happen to planes, this can also happen to ideas. Some of them take some time to be shot down, but sometimes they it takes less time. Who would have thought that some are shot down before they take off!
This is super scientific so read on if interested
When I was a “scientific-ameoba” there was an idea that suppression of T cells was controlled by a gene in the major histocompatibility complex of mice called I-J. People made their names working on this. But then came along moelcular biology and it was shown that I-J did not exist in the major histocompatibility complex….Now you never hear of I-J
So we pop over to ACTRIMS/ECTRIMS and virtualMS. This set of a discussion with ProfK
P0948 – CD20+ T cells emerge from pathogenic B cell- T cell interaction
Background: B cell depleting anti-CD20 antibodies (ab) are highly effective in multiple sclerosis (MS). Besides B cells, a population of pro-inflammatory T cells express CD20. The origin of these CD20 positive T cells and whether their depletion contributes to the clinical effect of anti-CD20 is unclear.
Objectives:This study is focused on characterizing CD20+ T cells both in naive and experimental autoimmune encepahalomyelitis (EAE) mice and in humans
Methods: CD20+ T cells were analyzed for their phenotype, cytokine expression and developmental state using flow cytometry, FACS, ELISA, RT pcr and microscopy. Spleens, inguinal lymph nodes, blood and spinal cord from wild type, 2D2 (MOG myelin specific T cell receptor transgenic mice) , µMT (B cell deficient) and CD20KO (CD20 deficient) mice as well as PBMCs (white blood cells) from MS patients were examined. Splenoculture and B cell-T cell coculture with 2D2 T cells and various B cells (wt, CD20KO, membrane stained) were used to analyze CD20 content and transfer. EAE was induced by immunization of the mice with CFA and MOG peptide.
Results. When compared to CD20- T cells, CD20+ T cells show enhanced features of pathogenicity both in mice as well as in patients with MS. In wild-type mice, CD20+ T cells expand during EAE, while B cell-deficient mice do not exhibit CD20+ T cells. T cells themselves are not able to generate CD20 and in splenocyte cultures, de novo development of CD20+ T cells is strictly dependent on the presence of B cells expressing CD20. In direct B cell-T cell cocultures, CD20 is transferred from B cells to T cells via trogocytosis (This is a process by which pieces of the cell membrane of one cell is clipped off and transferred to the other). Along the same lines, transfer of CD20 expressing B cells into B cell-deficient mice results in the development of CD20+ T cells.
Conclusions. CD20 on T cells relies on its transfer from B cells via trogocytosis. Thus, T cell CD20 is a marker for their recent activating interaction with a B cell, explaining the pronounced pro-inflammatory phenotype of these T cells. These data suggest that depletion of CD20+ T cells may substantially support the effectiveness of anti-CD20 ab therapy in MS, and their reappearance in the blood may serve as a marker for reemerging pathogenic B cell – T cell interaction.
So the T cells that have contacted B cells such as antigen presenting B cells are the important pathogenic cells. Therfore this minor T cell population could be the very important cell population activated by B cells. You dont need T cell therapy to get rid of them, you can just use the B cell depleting cells. Lovely,…..I thought I have to change my mind about stuff here. Here’s me thinking it is a Red Herring. CD8 T cells are the dominant T cells in MS lesions if you believe some pathologists and immunologists, we should be depleting CD8 T cells to get rid of MS?
I personally am concerned that this could be a bad idea because CD8 T cells are also regulators as well as anti-viral cells. Fear not, it’s not important what I think, I am sure it is being planned somewhere
However then I thought hang-on….Is this virtualMS stuff is too good to be true? The suggestion that cells are not able to generate CD20 does not fit with what has been reported previously.
Shuh et al. J Immunol 2016, 197:1111. https://doi.org/10.4049/jimmunol.1600089 T cells in humans can make CD20 message, they don’t make much CD19 message and so they could make CD20 protein. If T cells are so important in the anti-CD20 effect, why is anti-CD19 (CD20 B cells + a few more B cells) so effective. I guess the answer would be trogocytosis also but where are the CD19 T cells?
However trogocytosis of CD20 by T cells have been reported by others
However, others do not buy this idea. Proinflammatory CD20+ T cells in the pathogenesis of multiple sclerosis.von Essen MR, Ammitzbøll C, Hansen RH, Petersen ERS, McWilliam O, Marquart HV, Damm P, Sellebjerg F.Brain. 2019 Jan 1;142(1):120-132. doi: 10.1093/brain/awy301
They say “Recent studies have established the existence of a T cell subset expressing low levels of CD20; however, there have been discrepancies about the origin of these cells. Bremer and co-workers suggested that the CD20 molecule was transferred from B cells to T cells in a process termed trogocytosis (de Bruyn et al., 2015). Various studies have documented MS4A1/CD20 mRNA (message that is made into protein) in CD20+ T cells and furthermore CD20+ T cells have been found in the thymus where B cells are not present (Wilk et al., 2009; Schuh et al., 2016); trogocytosis therefore unlikely accounts for the majority of CD20 expressed on the surface of CD20+ T cells. In agreement with these observations we and others (Palanichamy et al., 2014) found that CD20 is expressed in both naïve (not activated yet) and memory T cells and that only a small fraction of CD20+ T cells express activation markers; trogocytosis only takes place following T cell receptor triggering. From these observations we hypothesized that CD20+ T cells represent a distinct cell lineage. Krumbholz and coworkers observed CD20+ T cells in thymic samples from very young children (<93 days old) (Schuh et al., 2016) strengthening the perception of CD20+ T cells being a cell lineage; and implying that CD20+ T cells develop very early in life. Analysing cord blood samples from newly born individuals, however, showed that we are not born with CD20+ T cells”……..De De derrrrr!
OK this is abit dogmatic too as there are plenty of reports of B cells in the thymus of mice and humans, but then this weeks news from the Netherlands, they find CD20 T cells in the brains of MS and in fact the extract live CD8 T cells from MS brains and they are making CD20. These were in lesions. Does this come from B cells…I’m not convinced. But let’s wait until it comes out in I can guess where. I will then ask who reviews this stuff!. The T cellsers will lap it up and I will be wondering why we have to make a difficult and implausible explanation (to suggest that T cells are doing the business) when a much easier one can be made. Furthermore, CD8 is found on lower levels on CD4 T cells than CD8 T cells, so why CD4 Th17?
White matter lesions in multiple sclerosis are enriched for CD20(dim) CD8(+) tissue-resident memory T cells.Hsiao CC, Fransen NL, van den Bosch AMR, Brandwijk KIM, Huitinga I, Hamann J, Smolders J.Eur J Immunol. 2020 Sep 19. doi: 10.1002/eji.202048665. Online ahead of print.
What do you think? CD20T cells come from B cells and no need for extra T cell therapy or should we put effort into determining what CD8 T cells do?