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Seminars in Immunology 20 (2008) 157–158

Contents lists available at ScienceDirect

Seminars in Immunology

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IV and the architecture of immune responses

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In this issue we have tried to address a key puzzle in themmunopathology of HIV-dependent immunodeficiency: why lossf CD4 memory T cells in that disease is closely associated with theisintegration of the normal architecture of secondary lymphoidissues. We initially hoped Jon Heeney would contribute to thisssue but unfortunately he was not able to do this; hence the slightlyhin nature of this volume. Working with the natural simian hosts ofIV1, the chimpanzee, he and others made the seminal observation

hat lymphoid tissue disorganization did not occur in chimpanzees1] which unlike humans fail to develop the profound immunodefi-iency associated with AIDS despite evidence of infection of CD4 Tells. Similar observations have been made by others in the naturalosts of HIV2, Sooty Mangabeys [2]. As lymphoid tissue disorgani-ation cannot be explained by loss of CD4 T cells alone, other cellularechanisms must account for this particular immunopathology. In

his issue we bring together two distinct areas of research: thoseorking on lymphoid tissue development and organization; and

hose trying to understand the disruption to the architecture ofymphoid tissues in HIV.

. Lymphoid tissue inducers in adaptive CD4-cell-dependent responses

In the first contribution, Lane and colleagues group highlightshe potential of lymphoid tissue inducer cells (LTi) to contribute toIV-mediated immunopathology. In development, through theirxpression primarily of lymphotoxins, LTi orchestrate with stromalells the development of lymph nodes and gut-associated lymphoidtructures including Peyer’s patches and isolated lymphoid folli-les. Data from our group but also others has shown that theseells persist in adulthood, where they continue to be involved inaintaining lymphoid tissue architecture. More importantly, forIV-mediated immunopathology, these cells in adult are linkedith maintenance of CD4 memory T cells. As these cells in mice

xpress both CD4 and the chemokine receptors CXCR4 and CCR5,e suggest that deletion of the human equivalent during HIV infec-

ion would help explain the loss of organization and CD4 memoryuring progression to immunodeficiency in untreated HIV disease.

. Development of human lymph nodes and Peyer’s patches

In the second contribution, Tom Cupedo reviews the data inuman and mice on the role of LTi in lymphoid tissue develop-

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ent. Although there is an extensive literature on mouse LTi, theame cannot be said for humans. Literally the field is wide open.ecause of the difficulties in obtaining human tissue for scientificesearch there are considerable obstacles to progress in this area.owever, Tom Cupedo suggests transplanting human tissues into

mmunodeficient mice offers hope of identifying human LTi.

. Homeostatic chemokines in development plasticity, andunctional organization of the intestinal immune system

The human intestine is a major target for HIV during acute infec-ion with massive depletion of CD4 T cells in this location acutelyollowed by continuing evidence of gut mediate immunopathologyt all stages of disease. In the third contribution, Reinhold Forsteromprehensively reviews the cellular and molecular mechanismshat orchestrate the development of normal gut associated lym-hoid tissues.

. The role of collagen deposition in depleting CD4+ T cellsnd limiting reconstitution in HIV1 and SIV infectionshrough damage to the secondary lymphoid organ niche

In the fourth contribution, the serious HIV biologists get theirhance to explain the lymphoid tissue abnormalities in HIV. Timo-hy Schacker points out CD4 T cell recovery is not inevitable in HIV.

ith Ashley Haase and Jacob Estes, they put forward the “damagediche hypothesis”. Although the cellular explanations are different,his conceptually is not so very different from what we proposeith LTi. They argue that destruction of the stromal infrastructureroducing cytokines and chemokines that recruit and sustain CD4cells underlies the genesis of the immunodeficiency. All we sug-

est is that there is a LTi sandwiched between the stromal cellnd the CD4 T cell. Nevertheless, these authors make the impor-ant point that the inflammation and fibrotic destruction of lymphodes would explain loss of the capacity to sustain CD4 T cells evenfter effective antiretroviral therapy.

. The lymph node in HIV pathogenesis

In the fifth chapter, Michael Lederman and Leonid Margoliseview the differences in immunopathology between humans andacaques, the non-natural hosts of HIV and SIV, and the natural

osts that fail to get the disease. They again point out that fibrosis

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58 Editorial / Seminars in Im

s linked with pathological progression. They also emphasize thatmmune activation and premature death of memory CD4 T cells areonsistent features of progressive disease.

In summary, a number of mechanisms have been proposed toxplain the CD4 deficiency that develops during the course of HIVnfection. The key point that we make in this volume is that diseases caused by failure of infrastructure to sustain CD4 T cells ratherhan direct infection of CD4 T cells alone.

. Lymph node architecture collapse and consequentodulation of FOXO3a pathway on memory T and B cells

uring HIV infection

In the final chapter, Sékaly and colleagues, also address the issuef lymphoid tissue destruction in the support for T and B cell mem-ry. They highlight that in humans that fail to progress to AIDS, asn primates, lymphoid tissue architecture is preserved. They par-icularly illuminate the role of the transcription factor Foxp3 in theeneration of B and T cell memory.

eferences

1] Koopman G, Haaksma AG, ten Velden J, Hack CE, Heeney JL. The relativeresistance of HIV type 1-infected chimpanzees to AIDS correlates with themaintenance of follicular architecture and the absence of infiltration by CD8+cytotoxic T lymphocytes. AIDS Res Hum Retroviruses 1999;15:365–73.

2] Hirsch VM. What can natural infection of African monkeys with simian immun-odeficiency virus tell us about the pathogenesis of AIDS? AIDS Rev 2004;6:40–53.

logy 20 (2008) 157–158

Peter Lane ∗

MRC Centre for Immune Regulation, Institute for BiomedicalResearch, Birmingham Medical School, Vincent Drive, Birmingham

B15 2TT, UK

Rafick-Pierre Sékaly a,b,c,d,∗∗a Laboratoire d’Immunologie, Centre de Recherche, Hôpital Saint-Luc,

Centre Hospitalier de l’Université de Montréal, 264 BoulevardRené-Levesque Est, Montréal, Québec H2X 1P1, Canada

b Laboratoire d’Immunologie, Département de Microbiologie etd’Immunologie, Université de Montréal, 264 BoulevardRené-Levesque Est, Montréal, Québec H3T 1J4, Canada

c Institut national de la Santé et de la Recherche médicale U743,Centre de Recherche, Centre Hospitalier de l’Université de Montréal,

64 Boulevard René-Levesque Est, Montreal, Québec H2X 1P1, Canadad Département of Microbiology and Immunology, McGill University,

Montréal, Québec H3A 2B4, Canada

∗ Corresponding author. Tel.: +44 1214144078.

∗∗ Corresponding author at: Laboratoire d’Immunologie, Centre deRecherche, Hôpital Saint-Luc, Centre Hospitalier de l’Université de

Montréal, 264 Boulevard René-Levesque Est, Montréal, QuébecH2X 1P1, Canada.

E-mail addresses: p.j.l.lane@bham.ac.uk (P. Lane),rafick-pierre.sekaly@umontreal.ca (R.-P. Sékaly)