Malaria-Specific CD4+ T Cell Proliferation May Protect Against Childhood Malaria

The proliferation of malaria-specific cord blood CD4⁺ T cells is associated with protection from childhood malaria, particularly in the first 2 years of life, according to a study by Margaret E. Feeney, MD, and colleagues, published in a new edition of Science Translational Medicine.

“We have identified a population of fetal malaria-responsive T cells in infants born to mothers with active placental malaria that have phenotypic features of effector memory cells and a variety of inflammatory effector functions,” the study authors wrote. “Here, we add to our current understanding of how the fetus is capable of responding to pathogens by demonstrating effector memory differentiation, inflammatory cytokine production, and robust antigen-specific T cell proliferation after in utero exposure to malaria.”

Additionally, the investigators added that the “transplacental exposure of the fetus, as occurs with placental malaria, similarly results in limited exposure to blood-stage antigens and may, therefore, lead to priming of protective memory CD4⁺ T cells that can respond vigorously after re-exposure to malaria during infancy.”

In their study, investigators from California and Uganda sought to assess the impact of in utero exposure to malaria on fetal T cell immunity. To accomplish this, the investigators evaluated the frequency, phenotype, and function of central memory (T_CM), effector memory (T_EM), and effector memory RA+ (T_EMRA) CD4⁺ and CD8⁺ T cells in cord blood of infants (n = 182) who were born to women with placental malaria and without placental malaria in a malaria-endemic area of Uganda. Mothers were enrolled in a study regarding prenatal and early childhood malaria intermittent preventative treatment (IPT) and were assessed each month for malaria from baseline to delivery.

A significantly higher frequency of CD4⁺ T_EM cells were observed in infants who were born to women with active placental malaria vs without active placental malaria (P =.0001). Histopathology also visualized significantly higher frequencies of CD4⁺ T_EM cells among infants with parasite-containing placentas vs infants with placentas without parasites (P =.018). In an additional analysis which sought to determine the activation profile, differentiation status, and TH subset distribution of fetal non-naïve CD4⁺ and CD8⁺ T cells (T_EM, T_CM, and T_EMRA), the investigators found that CD4⁺ T_EM cells demonstrated the proapoptotic marker CD95/Fas, the high-affinity interleukin-2 (IL-2) receptor CD25, and the inhibitory receptor programmed cell death-1 (PD-1) compared with naïve T cells (T_N).

In addition, Dr. Feeney and colleagues observed that fetal CD4⁺ and CD8⁺ T cells had greater in vitro proliferation to malaria antigens if they were found among infants who were exposed to malaria while in the womb. High proliferation was associated with a greater than 70% lower malaria incidence within the first 2 years of life vs low proliferation (incidence rate ratio [IRR], 0.28; P =.02). Intermediate and high CD4⁺ T cell proliferation of malaria was also associated with a reduced time to malaria following birth compared with low proliferation (intermediate group: hazard ratio [HR], 0.40; P =.05; high group: HR, 0.28; P =.01). These findings, according to the investigators, suggest that malaria-specific CD4⁺ T cell proliferation exerts a potentially protective effect against childhood malaria.

A limitation of the analysis was the inclusion of only women who had received “the standard-of-care 3-dose IPT for malaria, providing some protection from malaria during pregnancy.”

Additionally, the investigators of the study noted that misdiagnoses were possible in this cohort, and the relatively small number of included infants, as well as the inclusion of only women from Uganda, may result in the reduced generalizability of the findings across the population.

“It is possible that malaria antigenemia from breakthrough infections may drive the differentiation of protective CD4⁺ T cell responses into regulatory IL-10—producing T_H1 cells, the predominant CD4⁺ T cell phenotype observed in highly exposed children,” the authors wrote. “Nonetheless, our findings raise the intriguing possibility that vaccination during pregnancy could benefit infants through the induction of fetal effector memory T cell responses.”

Reference:

Odorizzi PM, Jagannathan P, McIntyre TI, et al. In utero priming of highly functional effector T cell responses to human malaria. Sci Transl Med. 2018;10(463).