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B-cell help by Tc2 cells
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
cells~.
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Paganelli et al., unpublished).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
Vo|.
I I 9
the model system provided by AIDS with
9 9 8 No.3
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
conditions of extreme depletion of C D 4 Th cells can be efficiently supported by Tc2
factor (GM-CSF), macrophage inflammatory
cells~.
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
Vo|.
I I 9
the model system provided by AIDS with
9 9 8 No.3
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