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Home of immune memory found

New findings overturn a major model of where immune memory is stored. Rather than circulating throughout the body, as researchers had thought, memory T-cells actually reside in a comfortable niche in the bone marrow waiting for the next chance to fight infection, according to a linkurl:new article;http://www.cell.com/immunity/abstract/S1074-7613(09)00187-3 published online in __Immunity__ today (May 7th). "It's very exciting data," said Antonio Lanzaveccia from the Institute for Research in B

By | May 7, 2009

New findings overturn a major model of where immune memory is stored. Rather than circulating throughout the body, as researchers had thought, memory T-cells actually reside in a comfortable niche in the bone marrow waiting for the next chance to fight infection, according to a linkurl:new article;http://www.cell.com/immunity/abstract/S1074-7613(09)00187-3 published online in __Immunity__ today (May 7th).
"It's very exciting data," said Antonio Lanzaveccia from the Institute for Research in Biomedicine in Switzerland, who was not involved in the research. It would be important to see "what the relationship is between these memory cells and other memory cells that have been described," he added. Andreas Radbruch from the Charité German Rheumatology Center in Berlin and colleagues wanted to take a closer look at T memory cells because in earlier studies they had found that memory B-cells, which produce antibodies, reside in the bone marrow. Immunologists have long believed that memory cells come from activated effector T cells that have resigned their ability to fight, and simply remain in circulation until they are re-activated a second time by the same pathogen they initially attacked. Researchers have been able to easily isolate circulating memory T-cells in human subjects, said Lanzaveccia, but accessing bone marrow is much more difficult. To test whether memory T cells stayed in circulation or retreated to the bone marrow, Radbruch and first author Koji Tokoyoda, also at the German Rheumatology Center, infected a mouse with a pathogen, and then searched for the T-cells specific to that pathogen at different time points. As expected, the specific T-effector cells at first proliferated to fight the infection. Four days in, researchers detected the memory cells mainly located in the lymphoid organs and spleen. But 3-8 weeks after infection -- by which time the remaining cells would have turned into memory cells -- the researchers searched again for those pathogen-specific cells and found that more than 80% of them were now in the bone marrow. These cells remained there for up to 134 days -- the length of time the researchers tested. To make sure the cells they detected in the bone marrow were "true" memory cells, Radbruch and colleagues characterized their surface molecules and tested them for the characteristics of memory cells: lack of proliferation, decreased gene expression, and the ability to reactivate upon re-infection with the same pathogen they had initially encountered. The cells in the bone marrow passed all three tests. The remaining 20% of cells not in the bone marrow probably belonged to a subset of T-memory cells that had been reactivated or were reacting to chronic infection, Radbruch suggested. Radbruch and colleagues wanted to find out what attracted the memory cells to the bone marrow. The prime suspect: an adhesion molecule called alpha2 integrin. The molecule showed increased expression on memory cells, and its ligand is predominantly expressed in bone marrow tissue. Also, when the researchers blocked alpha2 integrin with an antibody, the cells no longer homed to the bone marrow. Researchers went on to characterize the interaction between the memory cells and their bone marrow niche. "What I find totally exciting about this [paper]," said Lanzaveccia, is that "it has very nice and quantitative data." The researchers counted the number of memory cells in the bone marrow, nestled in niches producing nurturing cytokines, to be as high as 5 million. The authors hypothesize that the bone marrow offers memory cells an environment rich in cytokines essential for their survival. IL-7, for example, richly present in bone marrow, helps T-cells that aren't actively proliferating, survive. The paper poses such a basic question in immunology, Radbruch said, that one of his reviewers had asked why no one has thought to do such an experiment before. "All the good papers are like that," said Lanzaveccia: They make an experimenter think, "Gosh I should have thought of that!"
**__Related stories:__***linkurl: Immune memory debate heats up;http://www.the-scientist.com/blog/display/55351/
[22nd January 2009]* linkurl: Separate and unequal;http://www.the-scientist.com/article/display/54197/
[February 2008]*linkurl:Natural killers have memory, too;http://www.the-scientist.com/news/display/23333/
[17th April 2006]
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Comments

Avatar of: anonymous poster

anonymous poster

Posts: 2

May 7, 2009

If this is the case then the MHC diversity which is used to infer parasite diversity may not be a true indicator. \n\nIt shows that the MHC diversity is only for those parasites at a time of study.\n\n
Avatar of: Hilary Butler

Hilary Butler

Posts: 15

May 8, 2009

I notice her references do not contain two studies by Markus Feuerer.\n\n1) 2001 PMID 11279612\n2) 2003 PMID 12910264\n\nBoth previously proved that primed memory T-cells preferentially migrate to bone marrow for retainment, in humans not mice.\n\nTokoyoda's references contain no mention of Feuerer's work. I would have thought that if you were going to look at something, you'd look to see if someone had already done that before. And that the peers, refereeing it, would have checked that out too.
Avatar of: Hilary Butler

Hilary Butler

Posts: 15

May 8, 2009

Characterization of CD4+ T cells in mouse bone marrow. I. Increased activated/memory phenotype and altered TCR Vbeta repertoire.\n\nPrice PW, Cerny J.\n\nEur J Immunol. 1999 Mar;29(3):1051-6.\n\nPMID: 10092110 [PubMed - indexed for MEDLINE]\n\nalso showed migration of memory T lymphocytes into the bone marrow of mice.\n\n
Avatar of: Hilary Butler

Hilary Butler

Posts: 15

May 8, 2009

Slifka also showed that specific memory T cells were found in the BM for extended periods and could adoptively transfer protection against chronic viral infection. Tokoyoda has a 1997 Slifka reference, but not this one:\n\nBone marrow is a major site of long-term antibody production after acute viral infection.\n\nSlifka MK, Matloubian M, Ahmed R.\n\nJ Virol. 1995 Mar;69(3):1895-902.\n\nPMID: 7853531 \n\nIt's free at Pubmed central.
Avatar of: Donald Duck

Donald Duck

Posts: 39

May 9, 2009

I don't know how hard it is to find previous experiments of a similar or identical nature, but I suspect that in this age it could be mighty difficult to find one of millions of projects that is similar to yours, even with databases. Cut these guys a little slack here.\n\n Besides, unless something is confirmed by other groups it can't be considered to be reliable.
Avatar of: Richard Jefferys

Richard Jefferys

Posts: 3

May 14, 2009

Cell Immunol. 1974 Jul;13(1):95-106.\n\nAntibody formation in mouse bone marrow. II. Evidence for a memory-dependent phenomenon.\n\nBenner R, Meima F, van der Meulen GM.\n\nThis study documented migration of mouse CD4 cells to the bone marrow after priming back in 1974. I agree with Hilary that this new paper seems a bit light on the discussion of the history as it pertains to CD4 T cells. It also doesn't discuss some of the issues you'd think deserve consideration, e.g. that BM seems a major site for central memory CD8 T cell proliferation while the paper reports that BM CD4 T cells were not central memory and were not proliferating. Also prior studies of CD4 memory in the BM have stated that the cells have an activated phenotype whereas this paper is saying the cells are all at rest. A recent study from Guido Silvestri's group also documented a higher proportion of proliferating CD4 T cells in the BM versus blood or as measured by both Ki67 expression and CFSE dilution:\n\nBlood, Jan 2009; 113: 612 - 621. \n\nBone marrow?based homeostatic proliferation of mature T cells in nonhuman primates: implications for AIDS pathogenesis\n\nMirko Paiardini, Barbara Cervasi, Jessica C. Engram, Shari N. Gordon, Nichole R. Klatt, Alagarraju Muthukumar, James Else, Robert S. Mittler, Silvija I. Staprans, Donald L. Sodora, and Guido Silvestri\n\nSo it looks like some more work is needed to fully sort out what is going on.
Avatar of: Hilary Butler

Hilary Butler

Posts: 15

October 26, 2009

To Donald.\n\n10 minutes in Pubmed suffices. All scientists know the relevant key words.\n\nThe claim is that the finding is new, which it is not.\n\nReinventing the wheel is an expensive time-waster. By ignoring medical history, scientists can't accurately refine work by exploring known anomalies, or thinking through previous data, and with innovative lateral thinking, proposing and testing new immunological pathways, to expand horizons of knowledge.\n\nThis study is a classic example of such shortcomings.\n\nThis study doesn't add much at all to previous information at the end of a mouse, let alone indepth reading.\n\nThis topic is crucial in the long run, because so often an immunologist will say that "because there are detectable antibodies, a person is susceptible to disease."\n\nYet there is no test for anamnestic responses ( **except say, a 'rechallenge', and a blood test, whereby you say, "Oh, see?? I had IMMUNITY after all!!! ** ). So the public assumes that immunity blood tests encompass all known parameters, when they are only the tip of the iceberg.\n\nFor all the years that memory immunity has been studied to try to work it out, you'd think that there would have been a lot more movement on the topic. You'd even think that perhaps someone would come up with a valid, non-invasive test for it!\n\nHowever, it could be said that so long as ignorance is bliss, the blind can continue to lead the blind.
Avatar of: Hilary Butler

Hilary Butler

Posts: 15

October 26, 2009

"because there are ** NO ** detectable antibodies, a person is susceptible to disease."

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