Abstract
BackgroundEpidemiological studies suggest that allogeneic immunity may inhibit HIV-1 transmission from mother to baby and is less frequent in multiparous than uniparous women. Alloimmune responses may also be elicited during unprotected heterosexual intercourse, which is associated ex vivo with resistance to HIV infection.Methodology/Principal FindingsThe investigation was carried out in well-defined heterosexual and homosexual monogamous partners, practising unprotected sex and a heterosexual cohort practising protected sex. Allogeneic CD4+ and CD8+ T cell proliferative responses were elicited by stimulating PBMC with the partners' irradiated monocytes and compared with 3rd party unrelated monocytes, using the CFSE method. Significant increase in allogeneic proliferative responses was found in the CD4+ and CD8+ T cells to the partners' irradiated monocytes, as compared with 3rd party unrelated monocytes (p≤0.001). However, a significant decrease in proliferative responses, especially of CD8+ T cells to the partners' compared with 3rd party monocytes was consistent with tolerization, in both the heterosexual and homosexual partners (p<0.01). Examination of CD4+CD25+FoxP3+ regulatory T cells by flow cytometry revealed a significantly greater proportion of these cells in the homosexual than heterosexual partners practising unprotected sex (p<0.05). Ex vivo studies of infectivity of PBMC with HIV-1 showed significantly greater inhibition of infectivity of PBMC from heterosexual subjects practising unprotected compared with those practising protected sex (p = 0.02).Conclusions/SignificanceBoth heterosexual and homosexual monogamous partners practising unprotected sex develop allogeneic CD4+ and CD8+ T cell proliferative responses to the partners' unmatched cells and a minority may be tolerized. However, a greater proportion of homosexual rather than heterosexual partners developed CD4+CD25FoxP3+ regulatory T cells. These results, in addition to finding greater inhibition of HIV-1 infectivity in PBMC ex vivo in heterosexual partners practising unprotected, compared with those practising protected sex, suggest that allogeneic immunity may play a significant role in the immuno-pathogenesis of HIV-1 infection.
Highlights
Allogeneic immunity is the most potent natural immune response, as is observed in rejection of foreign tissues or organ transplants
The regulatory T cells were examined for the expression of CD40L, which in the steady state was found in 7.6(60.2)% CD4+CD25+FoxP3+ T reg cells and 28.9(61.1)% CD4+CD25+FoxP32 effector cells
Co-culture of allogeneic stimulated DC with autologous CD4+ T cells induced a greater proportion of CD4+CD25+FoxP3+ T reg cells expressing CD40L, whereas the reverse was found with the CD4+CD25+FoxP32 effector T cells
Summary
Allogeneic immunity is the most potent natural immune response, as is observed in rejection of foreign tissues or organ transplants. Natural allogeneic tolerance can be robust, as is seen in maternal tolerance of the fetal paternal semiallogeneic HLA. These two reciprocal mechanisms have occupied the central stage of immunology. Immunoregulatory CD4+CD25+FoxP3+ T cells (Tregs) have greatly influenced the concept of suppression of immune responses, and are known to inhibit autoimmune diseases [3,4,5] and elicit transplantation tolerance [6,7]. Alloimmune responses may be elicited during unprotected heterosexual intercourse, which is associated ex vivo with resistance to HIV infection
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