Dysregulation of CD4+CD25+CD127lowFOXP3+ regulatory T cells in HIV-infected pregnant women

Abstract

Pregnancy represents a major challenge to immunologic tolerance. How the fetal "semiallograft" evades maternal immune attack is unknown. Pregnancy success may involve alteration of both central (thymic) and peripheral tolerance mechanisms. HIV infection is characterized by CD4 ؉ T-cell depletion, chronic immune activation, and altered lymphocyte subsets. We studied immunologic consequences of pregnancy in 20 HIV-infected women receiving highly active antiretroviral therapy (HAART), and for comparison in 16 HIV-negative women. Lymphocyte subsets, thymic output, and cytokine profiles were measured prospectively during pregnancy and postpartum. A significant expansion of CD4 ؉ CD25 ؉ CD127 low FoxP3 ؉ regulatory T cells indicating alteration of peripheral tolerance was seen during second trimester, but only in HIVnegative women. HIV-infected women had lower CD4 counts, lower thymic output and Th-2 cytokines, and more immune activation at all time points compared with controls. Immune activation was decreased in HIV-infected patients during pregnancy. In contrast, CD4 counts were increased in both groups. In conclusion, the study does not indicate that pregnancy adversely affects the immunologic course of HIV infection. However, despite HAART during pregnancy, HIV-infected women display different immunologic profiles from HIV-negative women, which may have importance for the induction of fetalmaternal tolerance and in part explain the increased risk of abortion in HIVinfected women. (Blood. 2011;117(6): 1861-1868) IntroductionDuring pregnancy, the maternal immune system is exposed to a major challenge. The fetus expresses paternal alloantigens, yet it is not rejected. 1 The association between HY-restricting human leukocyte antigen (HLA) class II alleles and recurrent miscarriage subsequent to a firstborn boy indicates a CD4 ϩ T cell-mediated mechanism in these cases. 2 How the fetus normally evades a maternal immune response is not fully known, but development of fetal-maternal tolerance possibly relies on alterations of both central (thymic) tolerance 3-6 and peripheral tolerance mediated by regulatory T cells (Tregs). [7][8][9][10][11] The thymus is reduced in size and changed in structure during pregnancy, and in mice a substantial loss of thymocyte proliferation occurs from early pregnancy. 5,6,12 This may promote survival of the fetus by reducing production of new potentially fetus-reactive T cells. Both thymic size and function return to normal postpartum. 6 Likewise, peripheral tolerance is altered during pregnancy; levels of Tregs are expanded during both murine and human pregnancy. [7][8][9][10][11] This expansion is crucial to fetal survival, and lack of mobilization of Tregs may terminate the pregnancy in abortion. 7,9 A delicate balance of Th1-Th2 cytokines directed toward a Th2-dominant pattern is also considered a very important mechanism in favor of pregnancy success. [13][14][15] Knowledge of immunologic changes during pregnancy in HIV-infected women is limited. An increased risk of spontaneous abor...

Dynamics of Regulatory T-Cells during Pregnancy: Effect of HIV Infection and Correlations with Other Immune Parameters

“…This included CD4+CD25+FoxP3+, CD8+CD25+FoxP3+, CD4+TGFβ+ and CD4+IL10+ Treg and it was most likely an effect of HIV infection, which is in agreement with previous findings in non-pregnant HIV-infected adults [6], [8], [44], [45]. Our findings, however, contrast with a recently published study of pregnant women, which showed lower CD4+CD25+FoxP3+CD127 low Treg frequencies in HIV-infected compared with uninfected women during the 2nd trimester of pregnancy[46]. The duration of HAART of the HIV-infected subjects differed between the two studies, with most of our subjects starting HAART during pregnancy, while in the study by Kolte et al, most subjects were on HAART before pregnancy.…”

Peripheral Blood Cell Signatures of Plasmodium falciparum Infection during Pregnancy

“…The anti-inflammatory functions of Treg involve production of, for example, cytokines such as IL-10, which could at least partially explain the increased concentrations of IL-10 we observed in peripheral plasma in parallel with the different chemokines mentioned earlier (Boström S & Ibitokou S, unpublished data). The impact that any of the infection-mediated changes in circulating Treg observed here may have on the reported gestational age-related fluctuations in the frequency of Treg in PBMC during normal, healthy pregnancies remains to be determined [4], [47], [48]. Whether such fluctuations occur during ‘normal’ healthy pregnancies in African populations in any case requires confirmation.…”

Incidence of Pregnancy After Antiretroviral Therapy Initiation and Associated Factors in 8 West African Countries

“…Although systematically confirmed clinically, estimations on incidence rate of pregnancy presented in our study were initially based on women self-report of the last menstruation period. Bearing in mind that miscarriages and abortions are very frequent during the early months of pregnancy (27) and HIV infection has been pointed out as an important cause (28), we suspect that a substantial number of pregnancies may have gone undetected. The former and the significant proportion of dropouts contributed clearly to an underestimation of the pregnancy incidence reported.…”