T-cell modulation in decidua

T-cell modulation in decidua

letters high levels of interleukin 4 (IL-4), IL-5, 1L-10, granulocyte--macruphage colony-stimulating conditions of extreme depletion of C D 4 Th cell...

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letters high levels of interleukin 4 (IL-4), IL-5, 1L-10, granulocyte--macruphage colony-stimulating

conditions of extreme depletion of C D 4 Th cells can be efficiently supported by Tc2

factor (GM-CSF), macrophage inflammatory


protein lc~ (MIP-lcO, MIP-1[3 and RANTES, but no interferon -y (IFN-7) or IL-2, in the

Roberto Paganelli

We read with great interest the review by Mosmann and Sad t on factors determining

presence of anti-CD3 antibody (Ref. 3; R.

Enrico Scala

Paganelli et al., unpublished). Moreover,

Fernando Aiuti

the T helper 1 (Thl)/Th2 choice and the possible role of CD8 t T cells. The cognate

Massimo Fiorilli

B-cell helper function of CD8 ~ T cells pro-

their supernatants are capable of inducing in vitn~ IgE synthesis by normal B cells stimulated with anti-CD40 (Ref. 3). The constitu-

ducing type 2 cytokines (Tc2 cells) was regarded as unclear, due to the 'possible' ex-

clones, identified by the binding of a chimeric

B-cell help by Tc2 cells

pression of CD40 ligand (CD40L) 2 and the major histocompatibility complex (MHC) class I restriction of C D 8 cells. We have identified CD8'

Tc2 T-cell

clones in AIDS patients with hyper-IgE-like features and found that their phenotype

tive expression of CD40L by these T-cell fusion protein comprising human CD40 and mouse IgG1, results in clear-cut B-cell helper activity. The LAG-3 molecule, an MHC class II receptor preferentially expressed by activated CD8' T cells4,~, can provide a recognition system for cognate B-cell help.

was consistently CD45R0 *, CD25 ' , CD40L ~ and LAG-3 ~ (Ref. 3; E. Scala et al., unpub-

Thus, many components of Tc2-mediated B-cell help are indeed present at least in

lished). These Tc2 cells rarely occur in healthy ' individuals (although we have found some

hyper-IgE. These results support our view

clones in atopic young people) and produce

that in vivo production of lgE antibodies in

ronment at the time of antigen presentation

T-cell modulation in decidua The recent article by Raj Raghupathy I provides a convincing argument for a T helper 1 (Thl)-mediated mechanism in pregnancy failure. However, any consideration of immunomodulatory agents that induce a Th2 environment within decidua must include prostaglandin E2 (PGE2), which exerts a powerful influence by switching monocyte cytokine production2 and, moreover, could directly or indirectly induce anergy in uterine T cells. There is broad agreement that there are relatively few T cells in human firsttrimester decidua; thus, the majority of the critical cytokines, such as interleukin 10 (IL-10) and IL-12, will derive from macrophages since these are relatively abundant3. In this context, the main Th2inducing agent will be IL-10, which has already been given prominence in Raghupathy's articlel~ The hierarchical control of cytokine release from antigenpresenting cells (APCs), particularly the macrophage, will provide a cytokine envi-

~'l A t~ C i i 142


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the model system provided by AIDS with

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Dept of Clinical Medicine, University "La Sapienza', 1-00185 Rome, Italy. References 1 Mosmann, T.R. and Sad, S. (1996) lmmlmol. Today 17, 138-146 2 Cronin, D.C., Stack, R. and Fitch, EW. (19¢45) ]. [mmu~wl. 154, 3118-3127 3 Paganelli, R., Scala, E., Ansotegui, I.l-eta/. (1995) J. Exp. Med. 181,423M28 4 Baixeras,E., Huard, B., Miossec, C. ~'fat. (1992) J. Exp. Mcd. 176, 327-337 5 Huard, B., Tournier, M., Hercend. T., Triebel, E and Faure, E (1994) Eur. ]. [mmuptol. 24, 3216-3221

that is critical to the destiny of the T cell.

The second point is that the prominence of PGE and IL-10 in the decidual cytokine

Therefore, it is not surprising that PGE 2, as the major inducer of IL-10 in macrophages 2,

milieu might direct an alternative fate tor T cells interacting with APCs in decidua.

is well established as a significant decidual component4. In addition, the first-trimester

Although PGE and IL-10 induce a cytokine environment favouring Tb2 cells, a more important role might be to induce tolerance in T cells. Both IL-10 (Ref. 8) and PGE (Ref. 9) induce anergy, and inhibitors of PGE production prevent the establishment of anergy. The effect of PGE in inhibiting

villous trophoblast is a major source of this immunomodulator5. Recent reports have established that PGE not only stimulates IL-10 but is also a potent inhibitor of IL-12 (Ref. 2), effecting a change in the ratio of these cytokines that is probably the most powerful impetus to Th2 cells2C PGE induces such a switch at levels at least an order of magnitude lower than those needed to affect T cells directly and therefore the indirect effect, transmitted via APCs, is likely to be the most important. In this way, both trophoblast and maternal macrophages contribute to a cytokine environment in which Thl responses would be severely curtailed in normal, successful pregnancy. The critical feature of this model is that any potential T-cell responses, modulated at the APC, will be Th2 rather than Thl, either due to the direct action of cytokine at the time of antigen presentation or due to maturation of any dendritic cells in the presence of PGE (Ref. 7).

IL-12 might also be a critical contribution to the process since absence of IL-12 is a prerequisite for anergy "~. Antigen-specific anergy induced in T cells in the presence of IL-10 gives rise to a T cell that can be ckmally expanded, giving a unique cytokine profile: low IL-2 and IL-4, normal IL-5 and high IL-10 (Ref. 11). These cells have been designated 'Trl' to denote their regulatory function. Such an effect at the time of any local antigen (e.g. trophoblast) presentation would create a T-cell population with low proliferative capacity. However, any clonal expansion that did occur would benefit the conceptus by further production of IL-I// and possibly transfornqing growth factor [3, thus affecting responses of naive T cells ~. Such a concept is supported by the finding


that, in the mouse, maternal T cells are found that are unresponsive to paternal antigen. The prominent role that PGE could play in anergy induction in decidua might also be exercised following semen deposition in the lower female genital tract, leading to T cells that are specifically anergic to spermatozoal antigen 12. This would support the adage that Nature is economical with her mechanisms. The presentation of such antigens in the vagina and cervix would unavoidably be affected by the vast concentrations of PGE in human seminal plasma. Thus, studies of early decidua, trophoblast and human seminal plasma lead to the conclusion that PGE is a major modulator of the immune response in reproduction. Moreover, not only may PGE be the overriding inducer of the shift to the Th2

We read with interest the comments of Nancy Oppenheimer-Marks and Peter Lipsky on the migration of naive and memory T cells1. They suggest that analysis of proliferation properties, expression of cell-surface molecules and in vitro transendothelial migratory capacity indicates that memory T cells, and not naive T cells, preferentially enter inflammatory sites. They conclude that this notion contrasts with the view on the migration routes of naive and memory T cells proposed in our article2. This is not the case. In our article we outlined that, in order to define migration pathways, it is necessary to follow the traffic of labelled lymphocytes in vivo. Furthermore, we showed that such studies made two main points. First, both naive and memory T cells enter lymph nodes and Peyer's patches via high endothelial venules (HEVs), the respective extent being unknown at that time. Second, the available in viw) migration data do not permit a definitive conclusion as to what extent naive and memory T cells migrate through nonlymphoid tissues such as the skin; the migration of naive and

cytokine pattern but also, and perhaps most


References 1 Raghupathy, R. (1997) Immunol.Today 18, 478M-82 2 Kraan,T.C.T.M.V.,Boeije, L.C.M., Smeenk, R.J.T., Wijdenes,J. and Aarden, L.A. (1995) J. Exp. Med. 181,775-779 3 Loke, Y.W.and King, A. (1995)Human Implantation, Cambridge University Press

4 Tawfik,O.W., Hunt, J.S. and Wood, G.W. (1986) Am. ]. Reprod. Irnmunol. 12, 111-117 S Kelly,R.W.,Carr, G.G., Elliot, C.L., Tulppala, M. and Critchley, H.O.D. (1995) Hum. Reprod. 10, 3289-3292 6 Mosmann, T.R. and Moore, K.W. (1991) hnmunol. Today A49-A53 7 Kalinski, P., Hilkens, C.M.U., Snijders, A., Snijdewint, EG.M. and Kapsenberg, M.L. (1997) J. Immunol. 159, 28-35 8 Groux,H., Bigler,M., de Vries,J.E. and Roncarolo, M.G. (1996)J. Exp. Med. 184, 19-29 9 Mannie, M.D., Prevost, K.D. and Marinakis, C.A. (1995) Cell. Immunol. 160, 132-138 10 Van Parijs, L., Perez, V.L., Biuckians,A., Macki, R.G., London, C.A. and Abbas, A.K. (1997) J. Exp. Med. 186, 1119-1128 11 Groux,H., O'Garra, A., Bigler, M. et at. (1997) Nature 389, 737-742 12 Kelly,R.W.and Critchley,H.O.D. (1997) Hum. Reprod. 12, 2200-2207

memory T cells into inflammatory sites not even being mentioned.

Taken together, the present data demonstrate that both naive and memory T cells

Data published in the past year strongly

use the HEV route, although the percentage

support our view. For example, the migration pathways of naive and memory T cells were followed after injection into rats 3. Using

of memory T cells expressing L-selectin (necessary for the interaction with HEVs

relevant, a state of anergy in T cells.

Rodney W. Kelly Hilary O.D. Critchley* Medical Research Council Reproductive Biology Unit, *and the Dept of Obstetrics and Gynaecology, University of Edinburgh Centre for Reproductive Biology, 37 Chalmers St, Edinburgh, UK EH3 9EW.

quantitative immunohistology, it was shown at the level of HEVs that both naive and memory T cells enter various lymph nodes and Peyer's patches in considerable numbers. In addition, in human lymphoid tissue, memory T cells have been found in the immediate vicinity of HEVs, and other groups have recently made observations in mice that also suggest entry of memory T cells into lymph nodes and Peyer's patches via HEVs (Refs 4-6). Due to the low number of naive and memory T cells, we could not determine whether a preferential migration in the skin prevails for any particular T-cell subset u n d e r normal circumstances. However, we observed comparable numbers of naive and memory T cells migrating through another nonlymphoid tissue: the liver (J. Westermann and L. Pape, unpublished). Thus, the issue of naive and memory T-cell migration to nonlymphoid organs such as the skin remains to be studied, and can probably best be addressed by following labelled T-cell subsets using the sheep model7.

during entry) is significantly lower than that of naive T cells3. Thus, from the analysis of expression of adhesion molecules alone, one would have predicted a preferential entry of naive T ceils via HEVs. However, studies that have followed the traffic of these T-cell subsets in vivo have revealed a comparable entry via HEVs, confirming our view proposed two years ago 2. Thus, at the moment, it does not appear possible to define migration pathways of lymphocytes other than by following them in viz~o3.

JCirgen Westermann Ulrike Bode Reinhard Pabst Centre of Anatomy (4120), Medical School of Hannever, 30623 Hannover, Germany. References 1 Oppenheimer-Marks, N. and Lipsky, RE. (1997) lmmunol. Today 18, 456--457 2 Westermann, J. and Pabst, R. (1996) hmnunol. Today 17, 278-282 3 Westermann,J., Geismar, U., Sponholz, A.,


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