Escolar Documentos
Profissional Documentos
Cultura Documentos
18:367391
Copyright q 2000 by Annual Reviews. All rights reserved
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review this large and developing field. While we have tried to do justice to the
field as it now stands, inevitably we will have omitted some elements that merit
attention. Undoubtedly, these issues will surface in due course if they shed new
light on the complex and perplexing relationship between the maternal immune
system and the developing fetus.
As declared above, our goal is to focus on a specific issue: regulation of maternal T cell responsiveness during gestation. To this end, we address the impact of
pregnancy on maternal T cell responsiveness and, in particular, examine the critical role of inflammation and the innate immune system in this unique immunological situation. While it is necessary to emphasize results obtained from
experimental animal (mostly murine) models of pregnancy, we are aware of the
potential pitfalls of this selective approach. Where possible we refer to evidence
that lessons learned from animal models are relevant to human pregnancy, and
we identify controversies that arise from potential distinctions between mice and
humans. While our selective approach ignores other important aspects of reproductive immunology, we justify this on the grounds that T cells are critical mediators of immunity that lead to clearance of microbial infections, autoimmune
diseases, tissue transplant rejection, and, in some experimental systems, to tumor
regression. Lessons learned from studying how maternal T cell responsiveness is
controlled during pregnancy are likely to illuminate the role of T cell immunoregulation in these important immunological phenomena. Throughout this review
we consider the current status of the paradox of the fetal allograft, which has
been the dominant hypothesis driving research and debate in the reproductive
immunology field for the last four decades (10). However, we also synthesize
older with more contemporary ideas to elaborate a coherent rationale that explains
fetal survival and from which potential lessons for understanding other immunological phenomena involving regulation of T cell responsiveness also emerge.
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During the discussion that follows we use the paradigm of the fetus as a tissue
allograft tolerated by the mother, contrasting the immunological situation of a
fetus with that of a tissue allograft surgically transplanted onto a nontolerant
(allogeneic) recipient. Although some commentators now question the value of
this comparison (1, 5), it is a useful starting point to consider the immunogenetics
and immunobiology of the maternal-fetal relationship. To mimic the immunogenetics of pregnancy, the hypothetical donor graft should express two haploid
genotypes (paternal x maternal, F1) and the recipient should match one donor
haplotype (the maternal genotype). To aid our discussion, we provide a diagram
comparing processes in the afferent (antigen presentation leading to T cell activation) and efferent (T cell differentiation, migration, and effector functions)
phases of a T cell response that lead to T cellmediated rejection of tissue allografts (Figure 1). We consider whether these processes occur or are moderated
during gestation to explain fetal allograft survival. This diagram is based on current knowledge of processes that provoke T cell activation leading to tissue allograft destruction and rejection after transplantation (14, 15).
372
Figure 1 T cell immunobiology of tissue allograft rejection compared to the situation of the fetus. Tissue alloantigens (Ag) are delivered
to draining lymph nodes (LN) by donor or host APCs (step 1) where they encounter nave T cells (Tn). This leads to T cell activation and
differentiation (step 2) into cytotoxic (Tc) and helper (Th1 and Th2) T cells. Effector T cells (Tc and Th1) recirculate to donor graft tissues
or help B cells to produce antibodies (Ig), which contribute to the destruction of cells of donor origin (step 3). Evidence that steps 13 are
subject to regulation during the maternal-fetal relationship are considered in detail in the text. Two additional steps are also considered; step
4, Th2 dependent suppression of Th1 and Tc effector T cells, and step 5, direct access of Tn to fetal tissues avoiding the need to circulate
through LN.
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release by decidual macrophages, which precedes fetal loss (21). These findings
send clear messages that cytokine imbalances associated with inappropriate activation of macrophages and NK cells of the innate immune system are detrimental
to fetal survival in this experimental model. Indeed, a recent review proposes to
categorize cytokines and growth/differentiation factors as either deleterious (TNFa, IFN-c, IL-2) or beneficial (TGF-b, LIF, CSF-1, GM-CSF, IL-1, IL-3, IL-4, IL6, IL-10 and IFN-s) to fetal survival, implying a link between regulated activation
of cells that produce the second set of factors and fetal survival in normal pregnancies (22). As yet, it is unclear how dysregulated activation of NK cells and
decidual macrophages relate to the distinctions made between fetal and tissue
allografts by maternal T cells. Moreover, how relevant these observations are to
successful pregnancy remains to be seen, originating as they do from a single
murine mating combination. Indeed, IFN-c (23) and nitric oxide (NO) (24) production by maternal monocytes and uterine NK cells (25) that invade the decidua
shortly after implantation are features of normal pregnancies in mice. One problem is that it is not obvious whether cytokine imbalances are caused by inappropriate T cell responses or vice versa. Chaouat et al showed that spontaneous fetal
loss in the CBAxDBA/2 model was corrected by administering IL-10 or the
unusual interferon variant IFN-s, which is expressed in ruminant placentas (26).
Collectively, these results point to a critical role for the local inflammatory milieu
at the maternal-fetal interface, which might shape the context in which maternal
T cells encounter fetal alloantigens. We discuss this issue in more detail later.
Connections between the activation status of the innate immune system and
human pregnancy outcomes have been reviewed recently (9).
An increasing number of reports document spontaneous fetal loss syndromes
in matings involving gene-deficient (knockout) mice. In some cases, these syndromes arise from defective placental vascularization or fetal development rather
than immune dysfunction and are not discussed here. Mice deficient in the production of myeloid growth/differentiation factors, granulocyte-macrophage colony stimulatory factor (GM-CSF) and macrophage colony stimulatory factor
(CSF-1 or M-CSF), both exhibit poor reproductive performance. In GM-CSF
gene-deficient mice, the effects manifest as poor placental development, which
increases the rate of fetal loss and compromises fetal growth (27). CSF-1 gene
deficient mice exhibit low pregnancy rates and small litter sizes that might indicate
immune dysfunction leading to fetal rejection. However, the major effect of CSF1 deficiency in spontaneously mutant osteopetrotic (op/op) mice is on the frequency and rate of ovulation (28). This highlights a major difficulty in using
gene-deficient mice to assess requirements for successful pregnancy since total
loss of a cytokine or growth factor may result in multiple effects, with cumulative
impacts on reproductive performance, without necessarily compromising immunological protection of the fetus. Another technical problem is that many investigators assess reproductive performance in syngeneic or at least MHC-matched
mating combinations because nearly all gene-deficient (knockout) mice are generated on the 129/Sj (H-2b haplotype) background, which are then intercrossed
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with H-2b haplotype C57BL/6 mice to establish the lineage. Given the importance
of assessing the potential immunological stress due to parental genetic disparity,
it is imperative to examine the effects of gene deficiencies in allogeneic as well
as syngeneic pregnancies. Linked to this, it may also be necessary to determine
whether the effects of gene deficiencies manifest only when inherited as maternal
and/or paternal traits rather than as traits inherited from both parents.
Induced Fetal Loss and Tryptophan Metabolism Increased rates of fetal loss
are induced by injecting pregnant mice with IL-2, which promotes Th1-type T
helper cell responses at the expense of Th2-type responses (29). This reinforces
the view that a delicate immunological equilibrium is established during gestation
that can be subverted by inappropriate activation of monocytes or lymphocytes
of the innate or adaptive immune systems (30). However, definitive proof that
maternal T cells specific for paternally inherited alloantigens could be induced to
participate in immune responses leading to fetal rejection was not obtained until
recently. Experimental evidence supporting this view was obtained from studies
in which pregnant mice carrying syngeneic or allogeneic fetus were treated with
a pharmacologic inhibitor of an enzyme called indoleamine 2,3 dioxygenase
(IDO) (31), which is expressed by cells in the maternal decidua (32) and which
catabolizes tryptophan (33). This treatment induced uniform loss of allogeneic
fetuses, which was complete by gestational day 9.5 when pregnant mice were
exposed to IDO inhibitor at gestational day 4.5, the time of blastocyst implantation. Further, the same treatment had no effect on development to term of syngeneic fetus or allogeneic fetus carried by immunodeficient RAG-1 gene-deficient
mothers, which have no lymphocytes. The rationale for these experiments came
from studies on immunosuppressive human macrophages that prevent T cell activation in vitro by depriving T cells of tryptophan (34). These findings demonstrate
that allogeneic fetus are potentially vulnerable to maternal T celldependent processes that could provoke fetal loss, and cells expressing IDO and degrading
tryptophan provide protection from maternal T cells. Interestingly, golden hamsters placed on high tryptophan diets exhibited high rates of fetal loss in an earlier
study (35). This study was designed to test whether increased synthesis of serotonin analogues derived metabolically from dietary tryptophan would induce
rapid fetal loss due to non-immunological, pharmacologic effects on the placenta.
However, the outcome obtained can also be interpreted in terms of a link between
tryptophan metabolism and immunological protection of allogeneic fetus during
gestation. More studies are needed to determine whether these findings can be
generalized to other mouse mating combinations and to other mammalian species,
including humans. However, the observation that serum tryptophan levels
decrease progressively from the first trimester of human pregnancy provides circumstantial evidence that this link may be relevant to human pregnancy (36).
Recurrent Spontaneous Abortion in Humans Spontaneous human fetal loss is
a significant clinical problem. Some commentators estimate that early fetal loss
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allograft and describe recent experimental data that relate to regulation of maternal
T cell responsiveness during pregnancy. Our discussion focuses on studies of
murine pregnancy, which are amenable to genetic manipulation and intense
immunological scrutiny. We also discuss how immunological knowledge gained
from studying pregnancy might apply more generally to understanding T cell
regulation in other immunological phenomena.
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379
foreign alloantigens during pregnancy and after tissue engraftment (5, 60, 61).
Thus, while the anatomical organization of the maternal-fetal interface may have
evolved at least in part to minimize immunological contacts, this is an imperfect
strategy necessitating additional mechanisms to ensure fetal survival during gestation. The experiments cited above demonstrating maternal T cell awareness of
unprocessed fetal H-2Kb alloantigen (56, 57) or male H-Y peptide bound to unprocessed H-2Db (58) imply that fetal cells expressing MHC alloantigens alert maternal T cells to the presence of fetal MHC alloantigens. (A less likely explanation
which cannot be entirely ruled out is that MHC alloantigens shed from fetal cells
attach to maternal APCs.) Thus, the conclusion from these studies is that either
maternal T cells encounter fetal cells as they circulate through the maternal-fetal
unit (Figure 1, step 5) or fetal cells migrate to local draining lymph nodes where
they present fetal alloantigens to maternal T cells (step 2).
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The observation that human trophoblast cells express the nonclassical and
relatively nonpolymorphic MHC class I molecules HLA-G and, possibly, HLAE has inspired much research and speculation about their immunological significance, particularly with respect to their possible effect on maternal T cell
responses (66, 72). Recently, debate has focussed on their possible roles in regulating NK cell activity, rather than T cell responses (73, 74). This debate is
difficult to evaluate experimentally, largely because analogous MHC-like molecules and their receptors have not yet been identified in rodents. This last point
suggests either that immunological roles for HLA-G/E may have evolved after
rodent and primate ancestors diverged, or that rodent and human NK cell receptors
are no longer homologous. Perhaps these possible roles, if they can be demonstrated experimentally, are examples of processes that evolved due to the need to
protect more fetal mass for longer periods in larger mammalian species.
Fetal Microchimerism In the field of transplantation research, energetic efforts
are currently directed at the therapeutic potential of induced microchimerism for
prolonging survival of tissue grafts (75, 76). In pregnancy, maternal T cell tolerance must be induced and maintained either by fetal trophoblast cells or by
fetal cells that enter the maternal circulation and establish a reservoir of fetal cells
in maternal tissues that is either stable or continuously replenished. At present, it
is not clear which route is most critical. However, recent studies have generated
compelling evidence that fetal microchimerism affects the maternal immune system. Studies on pregnant women show that fetal cells appear in maternal circulation at an early stage in gestation and that genetic microchimerism persists for
many years after parturition (7780). An earlier study on pregnant mice by Bonney & Matzinger demonstrated that male fetal cells containing Y-chromosomal
DNA access maternal circulation in about 20% of immunocompetent mice and
in a higher proportion (;40%) of immunocompromised mice (60). These observations prompted the authors to conclude that fetal microchimerism could not
explain maternal T cell tolerance and that maternal T cell immunity eradicated
all traces of fetal cells in maternal circulation in most cases. However, this conclusion would seem incompatible with data showing that maternal splenic T cells
not only are aware of fetal alloantigens but are tolerized to them in all pregnant
mice (5658). These results can be reconciled by assuming that fetal cells migrating into maternal tissues excite a T cell response that results in T cell tolerance
and destruction of the fetal cells.This scenario might also help to explain why
maternal tolerance disappears shortly after parturition, in the study by Tafuri et
al, since a continuous supply of fetal cells may be necessary to maintain T cell
tolerance (56); T cell tolerance did, however, persist after parturition, as reported
in the recent study by Jiang & Vacchio (58).
More speculatively, it has also been suggested that circulating fetal cells may
help induce or maintain thymic involution that persists during human and animal
pregnancy, and that this may contribute to maternal T cell tolerance of the fetus
(81, 82) (although it is difficult to eliminate neuroendocrine effects and nonspe-
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ance) induced in vivo when nave T cells encounter APCs in the presence of
nondeleting monoclonal antibodies that block T cell activation (86).
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response is such that this awareness of antigenic difference is not allowed to lead
to fetal rejection.
385
cytes and was not antigen-driven (matings were syngeneic), it nonetheless raises
the possibility that Fas-L could modulate local T cell activation in the placenta.
Likewise, IDO has been described at the maternal-fetal interface in human placenta (32), where it may serve an immunosuppressive role (31).
Finally, the most recent and controversial suggestion concerning maternal tolerance of the fetus asks whether there may be a systemic perturbation of specific
T cell responses to fetal antigens. There is growing agreement that naive T cells
that do not receive their initial activation under the normal (i.e., proinflammatory)
conditions may be rendered unresponsive or anergic (reviewed in 105). Under
certain circumstances, tolerized or anergized T cells may spread their unresponsiveness to other T cells recognizing the same antigen or to additional clones
recognizing different, linked antigens (106, 107; and reviewed in 86). The mechanisms of these phenomena are not fully understood, but they suggest that there
may exist antigen-specific tolerogenic mechanisms independent of the general
bias toward Th2 in pregnancy.
Evidence that such tolerogenic mechanisms might operate during pregnancy
has been discussed above. Taken together, these findings suggest that the T cell
repertoire capable of responding to fetal antigens is made aware of the presence
of these antigens during pregnancy and rendered unresponsive to them in an
antigen-specific manner. Whether this condition arises by direct exposure of all
potentially responsive cells to antigen under tolerizing conditions or by tolerization of a subset of T cells with subsequent spread to the remainder of the repertoire
remains to be determined.
CONCLUSIONS
We propose that the key difference between the fetal allograft and a solid-organ
transplant lies not in the ability of the adaptive immune system to see and respond
to fetal alloantigens, but rather in the way in which the innate immune system
treats the presence of the fetus. The innate system is alerted and responds actively
to the fetal invasion, but the type of inflammation jointly created by fetally
derived cells and the maternal innate immune system is not a milieu in which
rejecting T cell responses are produced. However, far from being hidden from
the maternal adaptive immune system, fetal alloantigens are actively involved in
establishing a condition of antigen-specific tolerance during pregnancy.
ACKNOWLEDGMENTS
These studies were supported by grants AI44219. AI42247, HL60137, and
AI44759 from the National Institutes of Health, the Departments of Medicine and
Pediatrics, Medical College of Georgia and generous support from the Trustees
of the Carlos and Marguerite Mason Trust.
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LITERATURE CITED
1. King A, Loke YW. 1999. The influence
of the maternal uterine immune response
on placentation in human subjects. Proc.
Nutr. Soc. 58:6973
2. Rinkevich B. 1998. Immunology of
human implantation: from the invertebrates point of view. Hum. Reprod.
13:45559
3. Hunt JS, Robertson SA. 1996. Uterine
macrophages and environmental programming for pregnancy success. Am. J.
Reprod. Immunol. 32:125
4. Redline RW. 1997. The structural basis
of maternal-fetal immune interactions in
the human placenta. Curr. Top. Microbiol. Immunol. 222:2544
5. Olding LB, Papadogiannakis N, Barbieri
B, Murgita RA. 1997. Suppressive cellular and molecular activities in maternofetal immune interactions; suppressor
cell activity, prostaglandins, and alphafetoproteins. Curr. Top. Microbiol.
Immunol. 222:15987
6. Raghupathy R. 1997. Th1-type immunity
is incompatible with successful pregnancy. Immunol. Today 18:47882
7. Torry DS, McIntyre JA, Faulk WP. 1997.
Immunobiology of the trophoblast:
mechanisms by which placental tissues
evade maternal recognition and rejection.
Curr.
Top.
Microbiol.
Immunol.
222:12740
8. Yokoyama WM. 1997. The mother-child
union: the case of missing-self and protection of the fetus. Proc. Natl. Acad. Sci.
USA 94:59986000
9. Sacks G, Sargent I, Redman C. 1999. An
innate view of human pregnancy. Immunol. Today 20:11418
10. Medawar PB. 1953. Some immunological and endocrinological problems raised
11.
12.
13.
14.
15.
16.
17.
18.
19.
387
388
38.
39.
40.
41.
42.
43.
44.
45.
46.
MELLOR n MUNN
maternal-fetal interface. J. Immunol.
151:456273
Wegmann TG, Lin H, Guilbert L, Mosmann TR. 1993. Bidirectional cytokine
interactions in the maternal-fetal relationship: Is successful pregnancy a TH2
phenomenon? Immunol. Today 14:353
56
Piccinni MP, Beloni L, Livi C, Maggi E,
Scarselli G, Romagnani S. 1998. Defective production of both leukemia inhibitory factor and type 2 T- helper cytokines
by decidual T cells in unexplained recurrent abortions. Nat. Med. 4:102024
Vince GS, Johnson PM. 1995. Maternofetal immunobiology in normal pregnancy and its possible failure in recurrent
spontaneous abortion? Hum. Reprod.
10(Suppl.)2:10713
Shaarawy M, Nagui AR. 1997. Enhanced
expression of cytokines may play a fundamental role in the mechanisms of
immunologically mediated recurrent
spontaneous abortion. Am. J. Obst.
Gynec. 76:20511
Sacks GP, Studena K, Sargent K, Redman CW. 1998. Normal pregnancy and
preeclampsia both produce inflammatory
changes in peripheral blood leukocytes
akin to those of sepsis. Am. J. Obst.
Gynec. 179:8086
Redman CW, Sacks GP, Sargent IL.
1999. Preeclampsia: an excessive maternal inflammatory response to pregnancy.
Am. J. Obst. Gynec. 180:499506
Dekker GA, Sibai BM. 1999. The immunology of preeclampsia. Semin. in Perinatol. 23:2433
Hamamah S, Fignon A, Lansac J. 1997.
The effect of male factors in repeated
spontaneous abortion: lesson from invitro fertilization and intracytoplasmic
sperm injection. Hum. Reprod. Update
3:393400
Labarrere CA, Faulk WP. 1995. Intercellular adhesion molecule-1 (ICAM-1) and
HLA-DR antigens are expressed on
endovascular cytotrophoblasts in abnor-
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
389
390
75.
76.
77.
78.
79.
80.
81.
82.
83.
MELLOR n MUNN
human histocompatibility leukocyte antigen (HLA)-G-specific receptor expressed
on all natural killer cells. J. Exp. Med.
189:10931100
Fuchimoto Y, Yamada K, Shimizu A,
Yasumoto A, Sawada T, Huang CH,
Sachs DH. 1999. Relationship between
chimerism and tolerance in a kidney
transplantation model. J. Immunol.
162:570411
Simon AR, Warrens AN, Sykes M. 1999.
Efficacy of adhesive interactions in pigto-human xenotransplantation. Immunol.
Today 20:32330
Knight M, Redman CW, Linton EA, Sargent IL. 1998. Shedding of syncytiotrophoblast microvilli into the maternal
circulation in pre-eclamptic pregnancies.
Br. J. Obstet. Gynaecol. 105:63240
Lo YM, Corbetta N, Chamberlain PF,
Rai V, Sargent IL, Redman CW, Wainscoat JS. 1997. Presence of fetal DNA in
maternal plasma and serum. Lancet
350:48587
Lo YM, Hjelm NM, Fidler C, Sargent IL,
Murphy MF, Chamberlain PF, Poon PM,
Redman W, Wainscoat JS. 1998. Prenatal
diagnosis of fetal RhD status by molecular analysis of maternal plasma. New
Engl. J. Med. 339:173438
Evans PC, Lambert N, Maloney S, Furst
DE, Moore JM, Nelson JL. 1999. Longterm fetal microchimerism in peripheral
blood mononuclear cell subsets in
healthy women and women with scleroderma. Blood 93:203337
Clarke AG, Kendall MD. 1994. The thymus in pregnancy: the interplay of neural, endocrine and immune influences.
Immunol. Today 15:54551
Savion S, Toder V. 1995. Pregnancyassociated effect on mouse thymocytes in
vitro. Cell. Immunol. 162:28287
Remuzzi G. 1998. Cellular basis of longterm organ transplant acceptance: pivotal
role of intrathymic clonal deletion and
thymic dependence of bone marrow
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
microchimerism-associated tolerance.
Am. J. Kidney Dis. 31:197212
Ota H, Gotoh M, Ohzato H, He L, Tanigawa T, Nagano H, Dono K, Takeda Y,
Okuyama M, Shimizu J, Umeshita K,
Nakamori S, Sakon M, Nishisho I, Monden M. 1999. Microchimerism in thymus
is associated with up-regulated T helper
type 1 cytokine transcription during cardiac allograft rejection in rats. Transplantation 67:16573
Hill JA, Polgar K, Anderson DJ. 1995.
T-helper 1-type immunity to trophoblast
in women with recurrent spontaneous
abortion. JAMA 273:193336
Waldmann H, Cobbold S. 1998. How do
monoclonal antibodies induce tolerance?
A role for infectious tolerance? Annu.
Rev. Immunol. 16:61944
Janeway CA. 1992. The immune system
evolved to discriminate infectious nonself from noninfectious self. Immunol.
Today 13:1116
Ibrahim MAA, Chain BM, Katz DR.
1995. The injured cell: the role of the
dendritic cell system as a sentinel receptor pathway. Immunol. Today 16:18186
Matzinger P. 1994. Tolerance, danger,
and the extended family. Annu. Rev.
Immunol. 12:9911045
Fearon DT, Locksley RM. 1996. The
instructive role of innate immunity in the
acquired immune response. Science
272:5054
Fearon DT. 1997. Seeking wisdom in
innate immunity. Nature 388:32324
Nabors GS, Afonso LC, Farrell JP, Scott
P. 1995. Switch from a type 2 to a type
1 T helper cell response and cure of
established Leishmania major infection
in mice is induced by combined therapy
with interleukin 12 and Pentostam. Proc.
Natl. Acad. Sci. USA 92:314246
Afonso LCC, Scharton TM, Vieira LQ,
Wysocka M, Trinchieri G, Scott P. 1994.
The adjuvant effect of interleukin-12 in
a vaccine against leishmania major. Science 263:23537
101.
102.
103.
104.
105.
106.
107.
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CONTENTS
Discovering the Role of the Major Histocompatibility Complex in the
Immune Response, Hugh O. McDevitt
Receptor Selection in B and T Lymphocytes, David Nemazee
Molecular Basis of Celiac Disease, Ludvig M. Sollid
Population Biology of Lymphocytes: The Flight for Survival, Antonio A.
Freitas, Benedita Rocha
Nonclassical Class II MHC Molecules, Christopher Alfonso, Lars
Karlsson
Negative Regulation of Cytokine Signaling Pathways, Hideo Yasukawa,
Atsuo Sasaki, Akihiko Yoshimura
T Cell Activation and the Cytoskeleton, Oreste Acuto, Doreen Cantrell
The Specific Regulation of Immune Responses by CD8+ T Cells
Restricted by the MHC Class Ib Molecule Qa-1, Hong Jiang, Leonard
Chess
The Biology of Chemokines and their Receptors, Devora Rossi, Albert
Zlotnik
Dendritic Cells in Cancer Immunotherapy, Lawrence Fong, Edgar G.
Engleman
CD8 T Cell Effector Mechanisms in Resistance to Infection, John T.
Harty, Amy R. Tvinnereim, Douglas W. White
Glucocoricoids in T Cell Development and Function, Jonathan D.
Ashwell, Frank W. M. Lu, Melanie S. Vacchio
Molecular Genetics of Allergic Diseases, Santa Jeremy Ono
Immunology at the Maternal-Fetal Interface: Lessons for T Cell Tolerance
and Suppression, A. L. Mellor, D. H. Munn
Regulation of B. Lymphocyte Responses to Foreign and Self-Antigens by
the CD19/CD21 Complex, Douglas T. Fearon, Michael C. Carroll,
Michael C. Carroll
Regulatory T Cells in Autoimmunity, Ethan M. Shevach
Signal and Transcription in T Helper Development, Kenneth M. Murphy,
Wenjun Ouyang, J. David Farrar, Jianfei Yang, Sheila Ranganath,
Helene Asnagli, Maryam Afkarian, Theresa L. Murphy
The RAG Proteins and V (D) J Recombination: Complexes, Ends, and
Transposition, Sebastian D. Fugmann, Alfred Ian Lee, Penny E. Shockett,
Isabelle J. Villey, David G. Schatz
The Role of the Thymus in Immune Reconstitution in Aging, Bone
Marrow Transplantation, and HIV-1 Infection, Barton F. Haynes, M.
Louise Markert, Gregory D. Sempowski, Dhavalkumar D. Patel, Laura
P. Hale
Accessing Complexity: The Dynamics of Virus-Specific T Cell
Responses, Peter C. Doherty, Jan P. Christensen
The Role of Chemokine Receptors in Primary, Effector, and Memory
Immune Responses, Federica Sallusto, Charles R. Mackay, Antonio
Lanzavecchia
Phosphorylation Meets Ubiquiination: The Control of NF-Kappa-B
Activity, Michael Karin, Yinon Ben-Neriah
Reservoirs for HIV-1: Mechanisms for Viral Persistence in the Presence
of Antiviral Immune Responses and Antiretroviral Therapy, Theodore
Pierson, Justin McArthur, Robert F. Siliciano
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