CD4 T cells are required to fight malaria infection by promoting both phagocytic activity and B cell responses for parasite clearance. In Plasmodium chabaudi infection, one specific CD4 T cell subset generates anti-parasitic IFN-γ and the antibody-promoting cytokine, IL-21. To determine the lineage of these multifunctional T cells, we followed IFN-γ+ effector T cells (Teff) into the memory phase using Ifng-reporter mice. While Ifng + Teff expanded, the level of the Th1 lineage-determining transcription factor T-bet only peaked briefly. Ifng + Teff also co-express ICOS, the B cell area homing molecule CXCR5, and other Tfh lineage-associated molecules including Bcl6, the transcription factor required for germinal center (GC) T follicular helper cells (Tfh) differentiation. Because Bcl6 and T-bet co-localize to the nucleus of Ifng + Teff, we hypothesized that Bcl6 controls the Tfh-like phenotype of Ifng + Teff cells in P. chabaudi infection. We first transferred Bcl6-deficient T cells into wildtype hosts. Bcl6-deficient T cells did not develop into GC Tfh, but they still generated CXCR5+IFN-γ+IL-21+IL-10+ Teff, suggesting that this predominant population is not of the Tfh-lineage. IL-10 deficient mice, which have increased IFN-γ and T-bet expression, demonstrated expansion of both IFN-γ+IL-21+CXCR5+ cells and IFN-γ+ GC Tfh cells, suggesting a Th1 lineage for the former. In the memory phase, all Ifng + T cells produced IL-21, but only a small percentage of highly proliferative Ifng + T cells maintained a T-bethi phenotype. In chronic malaria infection, serum IFN-γ correlates with increased protection, and our observation suggests Ifng + T cells are maintained by cellular division. In summary, we found that Ifng + T cells are not strictly Tfh derived during malaria infection. T cells provide the host with a survival advantage when facing this well-equipped pathogen, therefore, understanding the lineage of pivotal T cell players will aid in the rational design of an effective malaria vaccine.

CD4 T cells orchestrate immunity against blood-stage malaria. However, a major challenge in designing vaccines to the disease is poor understanding of the requirements for the generation of protective memory T cells (Tmem) from responding effector T cells (Teff) in chronic parasite infection. Here, we use a transgenic mouse model with T cells specific for the Merozoite Surface Protein (MSP)-1 of Plasmodium chabaudi to show that activated T cells generate three distinct Teff subsets with progressive activation phenotypes. The earliest observed Teff subset (CD127−CD62LhiCD27+) are less divided than CD62Llo Teff and express memory genes. Intermediate (CD62LloCD27+) effector subsets include the most multi-cytokine producing T cells, while fully activated (CD62LloCD27−) Late effector cells have a terminal effector T cell phenotype (PD-1+, Fashi, AnnexinV+). We show that while IL-2 promotes expansion, it actually slows terminal effector differentiation. Using adoptive transfer, we show that only Early Teff survive the contraction phase and generate the terminal late effector T cell subsets, while in uninfected recipients, they become both central and effector Tmem. Furthermore, we show that progression towards full Teff activation is promoted by increased duration of infection, which in the long-term promotes Tem differentiation. Therefore, we have defined markers of progressive activation of CD4 effector T cells at the peak of malaria infection, including a subset that survives the contraction phase to make Tmem, and show that antigen and cytokine levels during CD4 T cell expansion influence the proportion of activated cells that can survive contraction and generate memory in malaria infection.

B cells play a critical role in the clearance of Pneumocystis (PC). In addition to production of PC-specific antibody, B cells are required during the priming phase for CD4+ T cells to expand normally and generate memory. Clearance of PC was found to be dependent on antigen specific B cells and on the ability of B cells to secrete PC-specific antibody, as mice with B cells defective in these functions or with a restricted B cell receptor were unable to control PC infection. Because PC-specific antiserum was only able to partially protect B cell deficient mice from infection, we hypothesized that optimal T cell priming requires fully functional B cells. Using adoptive transfer and B cell depletion strategies, we determined that optimal priming of CD4+ T cells requires B cells over the first 2–3 days of infection and that this was independent of the production of antibody. T cells that were removed from PC-infected mice during the priming phase were fully functional and able to clear PC infection upon adoptive transfer into Rag1−/− hosts, but this effect was ablated in mice that lacked fully functional B cells. Our results indicate that T cell priming requires a complete environment of antigen presentation and activation signals to become fully functional in this model of PC infection.

The cervix is divided into two morphologically and immunologically distinct regions, namely, (1) the microbe-laden ectocervix, which is proximal to the vagina, and (2) the “sterile” endocervix, which is distal to the uterus. The two cervical regions are bordered by the cervical transformation zone (CTZ), an area of changing cells, and are predominantly composed of cervical epithelial cells. Epithelial cells are known to play a crucial role in the initiation, maintenance, and regulation of innate and adaptive response in collaboration with immune cells in several tissue types, including the cervix, and their dysfunction can lead to a spectrum of clinical syndromes. For instance, epithelial cells block progression and neutralize or kill microorganisms through multiple ways. These (ways) include mounting physical (intercellular junctions, secretion of mucus) and immune barriers (pathogen-recognition receptor-mediated pathways), which collectively and ultimately lead to the release of specific chemokines and or cytokines. The cytokines subsequently recruit subsets of immune cells appropriate to a particular immune context and response, such as dendritic cells (DCs), T, B, and natural killer (NK) cells. The immune response, as most biological processes in the female reproductive tract (FRT), is mainly regulated by estrogen and progesterone and their (immune cells) responses vary during different physiological phases of reproduction, such as menstrual cycle, pregnancy, and post menopause. The purpose of the present review is to compare the immunological profile of the mucosae and immune cells in the ecto- and endocervix and their interphase during the different phases of female reproduction.

As effector memory T cells (Tem) are the predominant population elicited by chronic parasitic infections, increasing our knowledge of their function, survival and derivation, as phenotypically and functionally distinct from central memory and effector T cells will be critical to vaccine development for these diseases. In some infections, memory T cells maintain increased effector functions, however; this may require the presence of continued antigen, which can also lead to T cell exhaustion. Alternatively, in the absence of antigen, only the increase in the number of memory cells remains, without enhanced functionality as central memory. In order to understand the requirement for antigen and the potential for longevity or protection, the derivation of each type of memory must be understood. A thorough review of the data establishes the existence of both memory (Tmem) precursors and effector T cells (Teff) from the first hours of an immune response. This suggests a new paradigm of Tmem differentiation distinct from the proposition that Tmem only appear after the contraction of Teff. Several signals have been shown to be important in the generation of memory T cells, such as the integrated strength of “signals 1-3” of antigen presentation (antigen receptor, co-stimulation, cytokines) as perceived by each T cell clone. Given that these signals integrated at antigen presentation cells have been shown to determine the outcome of Teff and Tmem phenotypes and numbers, this decision must be made at a very early stage. It would appear that the overwhelming expansion of effector T cells and the inability to phenotypically distinguish memory T cells at early time points has masked this important decision point. This does not rule out an effect of repeated stimulation or chronic inflammatory milieu on populations generated in these early stages. Recent studies suggest that Tmem are derived from early Teff, and we suggest that this includes Tem as well as Tcm. Therefore, we propose a testable model for the pathway of differentiation from naïve to memory that suggests that Tem are not fully differentiated effector cells, but derived from central memory T cells as originally suggested by Sallusto et al. in 1999, but much debated since.