Mucosal Immunology Unit, Guy's, King's and St Thomas' Hospital Medical and Dental Schools, King's College London, London SE1 9RT, UK
Correspondence
Thomas Lehner
thomas.lehner{at}kcl.ac.uk
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ABSTRACT |
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INTRODUCTION |
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To the best of our knowledge there is no recorded evidence that mucosal alloimmunity has been investigated. This is somewhat surprising in view of the common exposure of vaginal and rectal mucosa to alloantigens in ejaculates. However, we recently reported that unprotected sexual intercourse with a monogamous partner elicited a significant alloimmune response to the partner's mononuclear cells, compared to unrelated cells (Peters et al., 2004). The CD4+ T cells from these women showed significant in vitro resistance to HIV-1 infection, compared with cells from those who practised protected sex.
Xenoimmunization of macaques with simian immunodeficiency virus (SIV) grown in human T cells has consistently been shown to protect the animals from SIV infection (Carlson et al., 1990; Desrosiers et al., 1989
; Langlois et al., 1992
; Murphey-Corb et al., 1989
; Stott et al., 1990
). There is also evidence that alloimmunization in macaques may protect them against SIV infection (Stott, 1994
). Antibodies to class I and class II molecules have been found in macaques immunized (Bergmeier et al., 1994
) or infected (Polyanskaya et al., 2003
) with SIV. Xenoimmunization of macaques significantly increased the concentration of CD8-derived suppressor factor (CD8-SF), CCL5, CCL3 and CCL4 (RANTES, MIP-1
and MIP-1
, respectively), which are associated with protection against SIV infection (Wang et al., 1998
). Furthermore, human in vitro studies suggest that alloantigens may induce HIV cross-reactive antibodies, cytotoxic lymphocytes or soluble factors (Bruhl et al., 1996
; Clerici et al., 1993
; Shearer et al., 1993
). Systemic alloimmunization in women revealed that the three CC chemokines are significantly upregulated and that the CCR5 (CC chemokine receptor 5) and CXCR4 co-receptors are downmodulated (Wang et al., 1999a
). Both M- and T-tropic HIV replication was inhibited in vitro by CD8-SF derived from peripheral blood mononuclear cells (PBMCs) of these women, in addition to a dose-dependent decrease in infectivity of CD4+ T cells.
Alloimmunization has been proposed as a strategy for inducing immune protection against HIV infection (Lehner et al., 2000a; Shearer et al., 1993
). Epidemiological evidence suggests that sex workers in West Africa who appear to be resistant to HIV infection express rare HLA alleles (Celum et al., 1994
). Transmission of HIV from mother to baby occurs more frequently among uniparous women (Kind, 1995
) and motherchild HLA class I concordance increases perinatal HIV-1 transmission (MacDonald et al., 1998
). Furthermore, selected sera from multiparous women showed significant CCR5 antibodies and in vitro inhibition of HIV-1 replication (Wang et al., 2002
). On the basis of these findings, we postulated that vaginal or rectal exposure to HLA antigens in ejaculates might elicit mucosal alloimmunity, generating CD8+ cell-derived antiviral factors and CC chemokines that affect immunity and transmission of the R5 strains of HIV.
The aim of this investigation was to determine in rhesus macaques whether rectal or vaginal mucosal exposure to allogeneic cells induced alloimmunity and affected SIV infectivity of CD4+ T cells. The results suggested that mucosal exposure to allogeneic cells in macaques elicited allogeneic T-cell proliferation, CD8+ cell-derived CC chemokines and antiviral factors, serum antibodies to CCR5 and a decrease in in vitro SIV infectivity of CD4+ T cells. However, major histocompatibility complex (MHC) typing of the macaques could not be done, because they were of Chinese origin for which typing reagents are not available, so the data should be interpreted with caution. In a further study of multiparous macaques in which natural alloimmunization may have been induced by the fetal semi-allogeneic cells, significant in vitro inhibition of SIV infectivity of CD4+ T cells was demonstrated, when compared with male macaques, as definitive nulliparous female macaques were not available.
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METHODS |
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T-cell proliferative response.
A one-way mixed lymphocyte reaction was used to stimulate 106 PBMCs with 106 irradiated allogeneic PBMCs. Briefly, the responder cells were made up to 106 cells ml1 in RPMI 1640, containing 2 mM glutamine and 100 µg penicillin and streptomycin (Sigma Fine Chemicals UK) ml1, with 10 % fetal calf serum (FCS). Stimulator cells from the allogeneic donor were prepared in the same manner and resuspended at a concentration of 106 cells ml1 in medium without FCS. Aliquots of 2x106 stimulator cells were irradiated for 15 min (40 Gy) using a caesium-137 source (Gammacell 1000 Elite; Norin International). The responder cells were plated out at a concentration of 105 cells per well and an equal number of irradiated stimulator cells was added to the appropriate wells in quadruplicate. Cultures were incubated at 37 °C for 4 days in 5 % CO2 and then pulsed with 10 µl [3H]thymidine for 16 h at 37 °C. Cultures were harvested on to glass fibre filters in a 96-well plate harvester (Micromate 96 Harvester; Packard). The results were read in a Matrix 96 direct -counter (Packard) and expressed as stimulation indices (SI), i.e. the ratio of counts of allostimulated and unstimulated PBMCs min1.
Generation of CD8-SF.
Generation of CD8-SF from a CD8+ T-cell enriched population was carried out as previously described (Cocchi et al., 1995; Lehner et al., 1996
; Mackewicz & Levy, 1992
). CD8+ cell populations were enriched by negative selection, using the panning method, as described previously (Lehner et al., 1996
). CD4+ cells were removed using a monoclonal antibody (mAb) against CD4 (OKT4 hybridoma culture supernatant), and monocytes and B cells were removed using antibodies against immunoglobulin (Serotec). The cells (>85 % CD8+ T cells) were then stimulated for 3 days with 10 µg phytohaemagglutinin (PHA; Sigma) ml1 in RPMI 1640 medium with 10 % FCS, supplemented with 2 mM glutamine and 100 µg penicillin and streptomycin ml1. PHA-stimulated CD8+ blasts were then washed and resuspended at a concentration of 2x106 cells ml1 in 10 % FCS/RPMI 1640 medium containing 10 % interleukin 2 preparation (IL2; Biotest UK). After 2 days of incubation at 37 °C in an atmosphere of 5 % CO2, the culture supernatant was collected and the cells replenished with fresh medium. This procedure was repeated up to three times. The collected supernatants were filtered through a 0·2 µm syringe filtration device and stored at 70 °C for the CD8-SF activity assay.
Assay of inhibition of SIV replication by CD8-SF.
Enriched CD4+ cells were prepared from simian PBMCs by negative selection using anti-CD8 mAb, as described above. CD4+ cells were stimulated for 3 days with 10 µg PHA ml1 in 10 % FCS/RPMI 1640. The cells were washed and pellets of 106 CD4+ cells were incubated with 100 µl SIVmac 251 stock preparation [containing 35 000 c.p.m. reverse transcriptase (RT) activity] for 3 h. After incubation, free virus was washed off with culture medium and 2x105 cells per well were plated on to 96-well tissue culture plates (Costar). To assay the activity of CD8-SF, 100 µl CD8+ cell-culture supernatant diluted 1 : 2 or 1 : 5 was added at the start of incubation to SIV-infected CD4+ cells. As a control, CD4+ cells were cultured in medium alone. After incubation for 2 days, 100 µl per well of the culture fluid was removed to monitor RT activity and replaced with 100 µl per well of diluted CD8+ cell supernatant (1 : 2 or 1 : 5) or control medium. This was repeated every 2 days for up to 14 days and the RT activity was determined using Quan-T-RT kits (Amersham).
Assay of CC chemokines.
The CC chemokines CCL5 (RANTES), CCL3 (MIP-1), CCL4 (MIP-1
) and CCL2 (MCP-1) were assayed in the culture supernatants generated by PHA stimulation of CD8+ T cells before and 1 month after each of the two alloimmunizations (Lehner et al., 1996
). Specific ELISA capture assays (R&D Systems) were used for the CC chemokines and the results expressed in pg ml1. Results are also presented for the combined concentration of CCL3, CCL4 and CCL5.
Preparation of CCR5 in baculovirus and antibody assay by ELISA.
CCR5 was generated in baculovirus and expressed in an insect cell line, as described previously for SIV gp120 (Doyle et al., 1995). Briefly, high-titre (109 p.f.u. ml1) baculovirus stock expressing CCR5 was used to infect insect cells for 2 days at 28 °C. Cells were harvested and CCR5 isolated. A recombinant baculovirus expressing CCR5His tag was prepared using the full-length gene of human CCR5, which was PCR cloned from pDNA3.1 CCR5 DNA (kindly provided by Dr John Moore, Department of Microbiology & Immunology, Weill Medical College of Cornell University, NY, USA) into the baculovirus transfer vector pAChis. The DNA construct was then used to form baculovirus expressing CCR5 with a six-His tag as described previously for SIV gp120 (Doyle et al., 1995
). Expression of the gene was confirmed by PCR and by immunostaining of the infected cells. Purification of the protein through binding of the six-His tag to nickelagarose was attempted but proved difficult under native conditions. Instead, we prepared CCR5 infected-cell lysates by three freezethaw cycles in 1 % Triton X-100/PBS. The purity of the baculovirus-prepared CCR5 has been demonstrated elsewhere (Lehner et al., 2001
). Antibodies to CCR5 were detected by ELISA by coating plates with baculovirus expressing CCR5 and with baculovirus alone. The plates were incubated with doubling dilutions of the serum samples. Bound antibody was detected by incubation with rabbit anti-monkey IgG (2 µg ml1; Sigma), followed by affinity-purified goat anti-rabbit IgGalkaline phosphatase conjugate (Sigma). IgG antibody titres are presented as reciprocals before and after each immunization.
SIV infectivity of CD4+ T cells in vitro.
CD4+ T cells were enriched from PBMCs by depletion of CD8+ cells, using mouse anti-monkey CD8 mAb (GM9 culture supernatant from the hybridoma), followed by goat anti-mouse antibody (STAR 87; Serotec), using the panning technique (Lehner et al., 1996). CD4+ cells (3x106 ml1) were activated with 10 µg PHA ml1 in 10 % FCS/RPMI 1640 for 3 days, and then washed with medium and cultured in RPMI 1640 with 20 % IL2 (Biotest UK) overnight. Serial dilutions of SIVmac 251 were prepared, with 30 000 c.p.m. RT activity per 100 µl. Aliquots of 0·6x106 cells were placed in universal tubes and infected with serial dilutions of SIV containing m.o.i. values of 101104 for 2 h. Cells were washed three times with medium and then cultured in triplicate at a concentration of 2x105 cells per well in 200 µl in 96-well culture plates. Every 3 days, 100 µl culture supernatant was replaced with 100 µl medium supplemented with 20 % IL2. On day 9, RT activity was assayed with the Quan-T-RT assay system (Amersham), using 70 µl cell-free culture supernatant per test. Results are presented as the mean (±SEM) of RT activity (c.p.m.) of three macaques before and after alloimmunization with 106 cells.
SIV infectivity of CD4+ T cells in multiparous macaques.
A group of five multiparous macaques was available, with recorded histories of three to five live births up to a year before their CD4+ T cells were examined for SIV infectivity. As we were unable to find nulliparous female macaques with a definitive history of no live or aborted fetuses, we used five male macaques as controls instead. The SIV infectivity of their CD4+ T cells was evaluated as described above.
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RESULTS |
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SIV infectivity of CD4+ T cells in macaques alloimmunized by the mucosal route
Analysis of SIV infectivity of PHA-stimulated CD4+ cells was carried out before and after alloimmunization with PBMCs in three macaques; two received 106 and one received 107 cells. The results suggest a dose-dependent inhibition of infectivity in the CD4+ T cells after alloimmunization, compared with those before alloimmunization (Fig. 4a). Thus, mucosal alloimmunization induced a decrease in SIV infectivity in CD4+ T cells separated from the circulating PBMCs. However, whether there was a similar or indeed enhanced inhibition of infectivity of CD4+ T cells in the mucosa or the regional lymph nodes was not ascertained.
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DISCUSSION |
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Investigation of CC chemokines derived by mitogenic stimulation of CD8+-enriched cells showed that CCL3, CCL4 and CCL5, but not CCL2, were significantly increased in concentration after both the first and second alloimmunizations. The response was dose-dependent, as was found with T-cell proliferation. The combined concentration of the three CC chemokines after the second immunization reached levels between 5453 and 14 466 pg ml1, which is within the range of 250025 000 pg ml1 required to inhibit 9095 % of SIV replication in vitro (Wang et al., 1999b). Hence, levels of CC chemokines can be reached that may inhibit SIV replication and this might also apply to the rectal and vaginal mucosa, as high numbers of CCL5- and CCL4-secreting cells were found in T cells eluted from the rectal mucosal tissue (Lehner et al., 2000b
). In addition to the CC chemokines binding CCR5 and preventing SIV transmission, CD8-SF was also significantly increased by alloimmunization and may contain other SIV inhibitory factors (Levy et al., 1996
). Recently, a protease inhibitor was reported to account for the anti-HIV activity generated from CD8+ T cells (Mackewicz et al., 2003
), as well as a ribonuclease (Rugeles et al., 2003
).
SIV infectivity of activated CD4+ T cells was then evaluated in vitro before and after mucosal alloimmunization. A significant dose-dependent inhibition of SIV infectivity of CD4+ T cells was found in alloimmunized macaques when compared with their pre-immunized cells. A similar inhibition of SIV infectivity of activated CD4+ T cells was found in multiparous macaques compared with male macaques. This suggests that alloimmunization of multiparous macaques by the semi-allogeneic fetuses had occurred which elicited inhibition of SIV infection of CD4+ T cells. However, the controls in this study were male macaques, as matched female nulliparous macaques were not available, it is most unlikely that the male macaques had been alloimmunized. Furthermore, we cannot be certain that the decrease in SIV infectivity in vitro will correlate with that found in vivo. Mucosal alloimmunization will now be investigated in Indian macaques, which will be challenged in vivo with SIV by the mucosal route of immunization.
In view of the antibodies elicited against CCR5 on xenoimmunization in macaques (Lehner et al., 1999) and alloimmunization in humans (Wang et al., 2002
), we examined the possibility that mucosal alloimmunization might also induce antibodies to CCR5. A dose-dependent increase in the titre of IgG antibodies to CCR5 was found in the sera of alloimmunized macaques, which may enhance blocking of CCR5 by CD8+ cell-derived CC chemokines and SF, thereby preventing SIV infection. Indeed, CCR5 antibodies enhance CC chemokine inhibition of SIV transmission (Lehner et al., 2001
). Anti-CCR5 antibodies are readily raised not only in macaques, but also in humans; indeed, antibodies to CCR5 have been detected in normal immunoglobulin used for therapeutic purposes (Bouhlal et al., 2001
). It is not clear why alloimmunization in contrast to auto-immunization should elicit CCR5 antibodies, but the most likely interpretation is that alloimmunization elicits cytokines and chemokines and upregulates co-stimulatory molecules, which may facilitate an immune response to CCR5 expressed on macrophages, dendritic cells and T cells. The mechanism responsible for preventing SIV or HIV infection is likely to be that of receptor dimerization (Vila-Coro et al., 2000
) and/or downmodulation of the cell-surface expression of CCR5 (Amara et al., 1997
; Mack et al., 1998
). However, antibodies to CCR5 may also block HIV transmission by steric hindrance.
The results of mucosal alloimmunization in macaques are consistent with systemic alloimmunization in humans, in whom increased CC chemokine, CD8-SF and CCR5 antibody levels and decreased infectivity of CD4+ T cells with HIV were found (Wang et al., 1999b, 2002
). Indeed, the results of direct mucosal alloimmunization are also consistent with the alloimmune responses elicited in humans practising unprotected sexual intercourse with significant in vitro resistance to HIV-1 infection (Peters et al., 2004
). Although we have not investigated directly the effect of mucosal alloimmunization on local mucosal immunity, the finding of systemic alloimmune responses and inhibition of SIV replication in circulating CD4+ T cells argue strongly in favour of local alloimmunization. We suggest that mucosal alloimmunization by HLA antigens in seminal fluid during unprotected sex may contribute to immune protection against HIV transmission, as has been widely reported in seronegative subjects at risk of HIV infection (Beyrer et al., 1999
; Garzino-Demo et al., 1999
; Goh et al., 1999
; Kaul et al., 2000
; Mazzoli et al., 1997
; Pinto et al., 1995
). This is potentially an important finding, as alloimmunization induces a powerful immune response and may be developed into a vaccination strategy to prevent or inhibit sexually transmitted HIV infection (Lehner et al., 2000a
). Mucosal alloimmunization with selected alloantigens that would cover 90 % of a given population needs to be explored.
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ACKNOWLEDGEMENTS |
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Wang, Y., Tao, L., Mitchell, E., Bravery, C., Berlingieri, P., Armstrong, P., Vaughan, R., Underwood, J. & Lehner, T. (1999a). Allo-immunization elicits CD8+ T cell-derived chemokines, HIV suppressor factors and resistance to HIV infection in women. Nat Med 5, 10041009.[CrossRef][Medline]
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Received 2 December 2004;
accepted 26 April 2005.
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