The cytotoxic potential of CD8+ T cells and NK cells plays a crucial role in the immune response to pathogens. Although in vitro studies have reported that CD4+ T cells are also able to mediate perforin-mediated killing, the in vivo existence and relevance of cytotoxic CD4+ T cells have been the subject of debate. Here we show that a population of CD4+ perforin+ T cells is present in the circulation at low numbers in healthy donors and is markedly expanded in donors with chronic viral infections, in particular HIV infection, at all stages of the disease, including early primary infection. Ex vivo analysis shows that these cells have cytotoxic potential mediated through the release of perforin. In comparison with more classical CD4+ T cells, this subset displays a distinct surface phenotype and functional profile most consistent with end-stage differentiated T cells and include Ag experienced CD4+ T cells. The existence of CD4+ cytotoxic T cells in vivo at relatively high levels in chronic viral infection suggests a role in the immune response.

1 Exograms, Interdisciplinarity, and the Cognitive life of Things The Extended Mind HypothesisOn the extended mind hypothesis (EM),l many of our cognitive states and processes are hybrids, unevenly distributed across biological and nonbiological realms (Clark 1997;Clark and Chalmers 1998). In certain circumstances, things-artifacts, media, or technologies-can have a cognitive life, with histories often as idiosyncratic as those of the embodied brains with which they couple (Sutton 2002a(Sutton , 2008. The realm of the mental can spread across the physical, social, and cultural environments as well as bodies and brains. My independent aims in this chapter are: first, to describe two compatible but distinct movements or "waves" within the EM literature, arguing for the priority of the second wave (and gesturing briefly toward a third); and, second, to defend and illustrate the interdisciplinary implications of EM as best understood, specifically for historical disciplines, by sketching two case studies.EM, an offshoot of mainstream functionalist information-processing cognitive science, has been focused in particular on our abilities to hook up with what Merlin Donald calls "exograms" or external symbols, by analogy with the brain's memory traces or "engrams" (Donald 1991, pp. 308-333; 2001, pp. 305-315).2 These abilities allow us to create and support cognitive profiles quite unlike those of creatures restricted to the brain's biological memories or engrams alone. Among other typical features, Donald pOints out that exograms last longer than engrams, have greater capacity, are more easily transmissible across media and context, and can be retrieved and manipulated by a greater variety of means (1991, pp. 315-316): so our skilled use of such crafted aids changes both the locus of memory in general and the role of our biological 190 J. Sutton memory within the new larger systems (see also Rowlands 1999, pp. 129-147).As I'll argue, it's important not to overstate the differences between internal and external traces: the version of EM I'm developing here, following in particular in Andy Clark's wake, is aimed precisely at investigating a wide range of possibilities on these and other dimensions of variation. I distinguish two versions or "waves" of EM, differentiated partly by the way these dimensions are characterized. These waves are not ultimately incompatible, but they are distinct strands in the EM literature and within Clark's own work: as we'll see, he acknowledged "a potential tension" between them as long ago as 1998 (Clark 1998, p. 99; see section 4 below). Before introducing the two waves, let me reiterate the key commitment they share, tweaked and applied differently in each case. External symbol systems and other "cognitive artifacts" are not always simply commodities, for the use and profit of the active mind: rather, in certain circumstances, along with the brain and body that interact with them, they are (part of) the mind. For Clark, "it is our basic human nature to annex, exploit and incorporate n...

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