Immune memory debate heats up

New findings stir the coals of a hot debate in immunology regarding the origin of memory T cells. The results, published in this week's Science, suggest that memory cells are descendant from the immune system's primary infection fighters, effector cells -- a finding which clashes with the two competing theories of memory cell origin, the authors say. Understanding these cells' origin could help researchers design cell-based vaccines, such as those in development for HIV. The initial response that leads to both memory and effector T cells begins in the lymph node. According to the text-book definition of these cells, effector cells leave the lymph node, while memory cells remain there, on-call to fight a secondary attack. Until recently, immunologists believed that memory cells stemmed from the handful of effector cells that remained after the effectors cleared a pathogen from the body. These left-over effector cells would de-differentiate -- or lose some of their effector functions -- and become memory cells capable of initiating a fast immune response the next time that pathogen appeared. This was termed the linear differentiation model. In 2007, however, immunologist linkurl:Steven Reiner;http://www.med.upenn.edu/immun/reiner.shtml from the University of Pennsylvania suggested that memory cells did not originate from effector cells, but rather from the same naive T cells as the effector cells. (Reiner wrote about linkurl:his work;http://www.the-scientist.com/2008/2/1/46/1/ in our February issue). Reiner's work suggested that effector and memory cells are created when proteins distribute unevenly between the progeny of the activated cell, a process known as asymmetric division. This is roughly similar to the way that stem cells divide to produce progeny, only neither of the daughter cells is identical to the parent cell. "That linkurl:paper;http://www.ncbi.nlm.nih.gov/pubmed/17332376?ordinalpos=18&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum was controversial," said Schoenberger. "A lot of people didn't want to believe that one cell has a number of fates available to it." In the current study, linkurl:Douglas Fearon;http://www.med.cam.ac.uk/html/PI/Fearon/index.html and colleagues at the University of Cambridge, UK, further addressed the question of memory cell origin by tracking the expression of granzyme B, a cytolytic molecule present in effector cells but generally lacking from memory cells. The researchers saw that some cells which stayed in the lymph node were able to turn on or off their granzyme B expression. Some of these cells also continued proliferating -- puzzling, since fully differentiated effector cells cannot proliferate. So what exactly are these cells? Fearon believes they have received stimulation to become effector cells, evidenced by the expression of granzyme B, but have not yet fully committed to terminal differentiation or of an effector or a memory cell. "Our study actually suggests that all memory cells have expressed granzyme B during primary clonal expansion," he said. That means that memory cells may come from cells that have at some point expressed one effector gene: granzyme B. It's not quite the linear differentiation model, but it does not support asymmetric division, said Fearon. But others researchers say the debate is far from settled. "[The authors] show that effector cells can become memory cells, but this doesn't mean that some memory cells are descended from precursors that never acquired effector functionality," said Stephen Schoenberger from the University of California, San Diego, who wrote an accompanying commentary on the article. Reiner, too, told The Scientist that he believes it would be premature to call the cells that remained in the lymph node "effectors," since he defines an effector as a cell that leaves the lymph node committed to fighting pathogen in peripheral tissue. "The fact that they're being saved [in the lymph node]" in itself implies they are not fully differentiated cells, but rather that they may be on the way to becoming either memory cells or effector cells. The results, Reiner says, do not discredit his asymmetric theory at all. The expression of granzyme B does not mean that the cell has committed to an effector fate. According to his research, the daughter cells of an activated T-cell divide granzyme proteins unevenly, rather than gene expression. It's very likely, he says, that both daughters (the one destined to become memory and the one destined for effector function) have an increased level of granzyme gene expression over the parent cell, but only one, he says will fully differentiate into an lymph-node exiting effector. The paper "doesn't close the book" on this debate, said Schoenberger, noting that "[it will] only compel more experimentation. Not a bad thing really."

Immune memory debate heats up

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