TB, or not TB: that is the question – does TLR signaling hold the answer?
Dec 16, 2004 - 6:02:38 PM

Defense against invading pathogens comes in two major forms: innate and adaptive immunity. Local barriers to infection such as the skin, and the production of stomach acid, mucous, tears, and saliva comprise what is known as innate immunity. This form of immunity is critically dependent on signaling by Toll-like receptors (TLRs) that rely heavily on an intracellular adaptor protein called myeloid differentiation factor 88 (MyD88). Acquired immunity is a form of cellular defense where foreign substances are attacked by lymphocytes and destroyed by T cells, and the adaptive immune response is also generally thought to require intact TLR-MyD88 signaling pathways.

However a study by Bernhard Ryffel and colleagues from Centre National de la Recherche Scientifique, France, in the December 15 issue of the Journal of Clinical Investigation, challenges this view and instead suggests that MyD88 may not be absolutely required for a normal adaptive immune response.

The authors used mice genetically deficient in MyD88 and subjected them to Mycobacterium tuberculosis infection. While their adaptive immune response appeared to be unaffected, markedly blunted defense by innate immune mechanisms eventually proved lethal. With the support of additional data, the authors concluded that MyD88-dependent signaling is not significantly involved in T cell activation (an adaptive immune response), but in the absence of MyD88, T cell–mediated immunity is only able to provide partial protection from infection.

This study suggests that we need to reassess whether adaptive immunity is really dependent upon innate immunity, and if MyD88 is not involved in regulating the adaptive response to M. tuberculosis infection, then what is? In an accompanying commentary, Terence Doherty and Moshe Arditi from Cedars-Sinai Medical Center in Los Angeles address these and other questions that arise from this study.

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