A dendritic cell targeted vaccine induces long-term HIV-specific immunity within the gastrointestinal tract

Despite significant therapeutic advances for HIV-1 infected individuals, a preventative HIV-1 vaccine remains elusive. Studies focusing on early transmission events, including the observation that there is a profound loss of gastrointestinal (GI) CD4⁺ T cells during acute HIV-1 infection, highlight the importance of inducing HIV-specific immunity within the gut. Here we report on the generation of cellular and humoral immune responses in the intestines by a mucosally administered, dendritic cell (DC) targeted vaccine. Our results show that nasally delivered α-CD205-p24 vaccine in combination with polyICLC, induced polyfunctional immune responses within naso-pulmonary lymphoid sites that disseminated widely to systemic and mucosal (GI tract and the vaginal epithelium) sites. Qualitatively, while α-CD205-p24 prime-boost immunization generated CD4⁺ T-cell responses, heterologous prime-boost immunization with α-CD205-p24 and NYVAC gag-p24 generated high levels of HIV-specific CD4⁺ and CD8⁺ T cells within the GI tract. Finally, DC-targeting enhanced the amplitude and longevity of vaccine-induced immune responses in the GI tract. This is the first report of a nasally delivered, DC-targeted vaccine to generate HIV-specific immune responses in the GI tract and will potentially inform the design of preventative approaches against HIV-1 and other mucosal infections.     

Modulation of immune responses through direct activation of Toll‐like receptors to T cells

Toll‐like receptors (TLRs), which are a family of pattern recognition receptors (PRRs), are involved critically in the generation and regulation of innate immunity as well as initiation of subsequent adaptive immune responses. However, recent research results showed that different subsets of T cells express certain types of TLRs during development and activation stages. Importantly, TLRs participate in the direct regulation of adaptive immune response, possibly as co‐stimulatory molecules. In this review we summarize recent studies about the novel regulation of TLRs on the homeostasis and immunity of different T cell subtypes including CD4⁺CD25⁺T regulatory cells (T_reg) and interleukin (IL)‐17‐producing CD4⁺T cells (T helper type 17). The direct involvement of TLRs in T cell‐mediated immunity prompted us to reconsider the role of TLRs in the occurrence of autoimmune diseases, infectious diseases and graft rejection. The important effects of TLRs in T cell‐intrinsic components also prompt us to explore novel vaccine adjuvants for modifying desired immune responses in an efficient way.     

HIV-1 and the hijacking of dendritic cells: a tug of war

Dendritic cells are critical for host immunity and are involved both in the innate and adaptive immune responses. They are among the first cells targeted by HIV-1 in vivo at mucosal sites. Dendritic cells can sequester HIV-1 in endosomal compartments for several days and transmit infectious HIV-1 to interacting T cells in the lymph node, which is the most important site for viral replication and spread. Initially, the cellular immune response developed against HIV-1 is strong, but eventually it fails to control and resolve the infection. The most dramatic effect seen on the immune system during untreated HIV-1 infection is the destruction of helper CD4⁺ T cells, which leads to subsequent immune deficiency. However, the immunomodulatory effects of HIV-1 on different dendritic cell subpopulations may also play an important role in the pathogenesis of HIV-1. This review discusses the effects HIV-1 exerts on dendritic cells in vivo and in vitro, including the binding and uptake of HIV by dendritic cells, the formation of infectious synapses, infection, and the role of dendritic cells in HIV-1 pathogenesis.     

The role of platelet CD154 in the modulation in adaptive immunity

Platelets’ primary role is hemostasis. However, a growing body of research has demonstrated that platelets are integral to the initiation of an inflammatory response and are potent effector cells of the innate immune response. Activated platelets express CD154, a molecule critical to adaptive immune responses, which has been implicated in platelet-mediated modulation of innate immune responses and inflammation. Recent studies utilizing CD154 knockout mice extend the role of platelet-derived CD154 to the modulation of adaptive immune response by enhancing antigen presentation, improving CD8⁺ T cell responses, and playing a critical function in T-dependent humoral immunity under physiological conditions. Together these data provide a basis for the expansion of the current paradigm of B cell activation and germinal center formation to include a role for platelets.     

Autophagy and adaptive immunity

Autophagy plays an important role in maintaining intracellular homeostasis by promoting the transit of cytoplasmic material, such as proteins, organelles and pathogens, for degradation within acidic organelles. Yet, in immune cells, autophagy pathways serve an additional role in facilitating intracellular surveillance for pathogens and changes in self. Autophagy pathways can modulate key steps in the development of innate and adaptive immunity. In terms of adaptive immunity, autophagy regulates the development and survival of lymphocytes as well as the modulation of antigen processing and presentation. Specialized forms of autophagy may be induced by some viral pathogens, providing a novel route for major histocompatibility complex (MHC) class I antigen presentation and enhanced CD8⁺ T-cell responses. Autophagy induction in target cells also increases their potential to serve as immunogens for dendritic cell cross-presentation to CD8⁺ T cells. The requirement for autophagy in MHC class II presentation of cytoplasmic and nuclear antigens is well established, yet recent studies also point to a critical role for autophagy in modulating CD4⁺ T-cell responses to phagocytosed pathogens. Autophagy pathways can also modulate the selection and survival of some CD4⁺ T cells in the thymus. However, much still remains to be learned mechanistically with respect to how autophagy and autophagy-linked genes regulate pathogen recognition and antigen presentation, as well as the development and survival of immune cells.     

Dendritic cells,T cells and their interaction in rheumatoid arthritis

Dendritic cells (DCs) are the key professional antigen-presenting cells which bridge innate and adaptive immune responses, inducing the priming and differentiation of naive to effector CD4⁺ T cells, the cross-priming of CD8⁺ T cells and the promotion of B cell antibody responses. DCs also play a critical role in the maintenance of immune homeostasis and tolerance. DC–T cell interactions underpin the generation of an autoimmune response in rheumatoid arthritis (RA). Here we describe the function of DCs and review evidence for DC and T cell involvement in RA pathogenesis, in particular through the presentation of self-peptide by DCs that triggers differentiation and activation of autoreactive T cells. Finally, we discuss the emerging field of targeting the DC–T cell interaction for antigen-specific immunotherapy of RA.     

Immune system development during early childhood in tropical Latin America: evidence for the age-dependent down regulation of the innate immune response

The immune response that develops in early childhood underlies the development of inflammatory diseases such as asthma and there are few data from tropical Latin America (LA). This study investigated the effects of age on the development of immunity during the first 5 years of life by comparing innate and adaptive immune responses in Ecuadorian children aged 6–9 months, 22–26 months, and 48–60 months. Percentages of naïve CD4+ T cells declined with age while those of memory CD4⁺ and CD8⁺ T cells increased indicating active development of the immune system throughout the first five years. Young infants had greater innate immune responses to TLR agonists compared to older children while regulatory responses including SEB-induced IL-10 and percentages of FoxP3⁺ T-regulatory cells decreased with age. Enhanced innate immunity in early life may be important for host defense against pathogens but may increase the risk of immunopathology.     

Two separate mechanisms of enforced viral replication balance innate and adaptive immune activation

The induction of innate and adaptive immunity is essential for controlling viral infections. Limited or overwhelming innate immunity can negatively impair the adaptive immune response. Therefore, balancing innate immunity separately from activating the adaptive immune response would result in a better antiviral immune response. Recently, we demonstrated that Usp18-dependent replication of virus in secondary lymphatic organs contributes to activation of the innate and adaptive immune responses. Whether specific mechanisms can balance innate and adaptive immunity separately remains unknown. In this study, using lymphocytic choriomeningitis virus (LCMV) and replication-deficient single-cycle LCMV vectors, we found that viral replication of the initial inoculum is essential for activating virus-specific CD8⁺ T cells. In contrast, extracellular distribution of virus along the splenic conduits is necessary for inducing systemic levels of type I interferon (IFN-I). Although enforced virus replication is driven primarily by Usp18, B cell–derived lymphotoxin beta contributes to the extracellular distribution of virus along the splenic conduits. Therefore, lymphotoxin beta regulates IFN-I induction independently of CD8⁺ T-cell activity. We found that two separate mechanisms act together in the spleen to guarantee amplification of virus during infection, thereby balancing the activation of the innate and adaptive immune system.     

Foxp3 and Treg cells in HIV-1 infection and immuno-pathogenesis

FoxP3⁺CD4⁺CD25⁺ regulatory T (Treg) cells are implicated in a number of pathologic processes including elevated levels in cancers and infectious diseases, and reduced levels in autoimmune diseases. Treg cells are activated to modulate immune responses to avoid over-reactive immunity. However, conflicting findings are reported regarding relative levels of Treg cells during HIV-1 infection and disease progression. The role of Treg cells in HIV-1 diseases (aberrant immune activation) is poorly understood due to lack of a robust model. We summarize here the regulation and function of Foxp3 in Treg cells and in modulating HIV-1 replication. Based on recent findings from SIV/monkey and HIV/humanized mouse models, a model of the dual role of Treg cells in HIV-1 infection and immuno-pathogenesis is discussed.     

Novel role of regulatory T cells in limiting early neutrophil responses in skin

It is clear that CD4⁺ CD25⁺ Foxp3⁺ regulatory T (Treg) cells inhibit chronic inflammatory responses as well as adaptive immune responses. Among the CD4⁺ T‐cell population in the skin, at least one‐fifth express Foxp3. As the skin is constantly exposed to antigenic challenge and is a common site of vaccination, understanding the role of these skin‐resident Treg cells is important. Although the suppressive effect of Treg cells on T cells is well documented, less is known about the types of innate immune cells influenced by Treg cells and whether the Treg cells suppress acute innate immune responses in vivo. To address this we used a mouse melanoma cell line expressing Fas ligand (B16FasL), which induces an inflammatory response following subcutaneous injection of mice. We demonstrate that Treg cells limit this response by inhibiting neutrophil accumulation and survival within hours of tumour cell inoculation. This effect, which was associated with decreased expression of the neutrophil chemoattractants CXCL1 and CXCL2, promoted survival of the inoculated tumour cells. Overall, these data imply that Treg cells in the skin are rapidly mobilized and that this activity serves to limit the amplification of inflammatory responses at this site.     

A role for granulocyte-macrophage colony-stimulating factor in the regulation of CD8(+) T cell responses to rabies virus

Inflammatory cytokines have a significant role in altering the innate and adaptive arms of immune responses. Here, we analyzed the effect of GM-CSF on a RABV-vaccine vector co-expressing HIV-1 Gag. To this end, we immunized mice with RABV expressing HIV-1 Gag and GM-CSF and analyzed the primary and recall CD8⁺ T cell responses. We observed a statistically significant increase in antigen presenting cells (APCs) in the spleen and draining lymph nodes in response to GM-CSF. Despite the increase in APCs, the primary and memory anti HIV-1 CD8⁺ T cell response was significantly lower. This was partly likely due to lower levels of proliferation in the spleen. Animals treated with GM-CSF neutralizing antibodies restored the CD8⁺ T cell response. These data define a role of GM-CSF expression, in the regulation of the CD8⁺ T cell immune responses against RABV and has implications in the use of GM-CSF as a molecular adjuvant in vaccine development.     

Putative role of marginal zone B cells in pathophysiological processes

The maintenance of inner integrity of an organism is founded on the proper performance of two immunity branches, innate and adaptive immune responses. Recently, it became apparent that subset of splenic B cells named marginal zone B cells (MZB cells) exhibits unique developmental and functional features that bridge these two immunity branches. Strategically positioned at the site where blood and lymph are filtered, MZB cells represent a population of sentinels that rapidly proliferate and differentiate into IgM plasmablast cells when encountered with blood-borne, thymus-independent (TI) Ags. Moreover, MZB cells have intrinsic capability to induce potent CD4⁺ helper T cell response and cytokine production upon stimulation with soluble antigens. Due to their ability to overcome a time gap prior the establishment of the full adaptive response towards pathogens, MZB cells connect and direct innate and adaptive immunity. An additional interesting characteristic of MZB cells is capacity to function as regulatory cells in autoimmune processes. MZB cells may also contribute to the control of autoimmunity via the induction of tolerance by apoptotic cells. Importantly, in the clear association with inflammation and autoimmunity, MZB cells may transform into MALT lymphoma, representing a concurrence point for the infection, immunity and malignancy. This paper presents an insight into the complex biology of marginal zone B cells and their role in intertwining and directing innate and adaptive immune processes at the physiological and pathological level.     

Mechanisms of enhanced HIV spread through T-cell virological synapses

An elaborate network of cell–cell interactions in the immune system is essential for vertebrates to mount adaptive immune responses against invading pathogens. For lymphotropic viruses such as the human immunodeficiency virus type 1 (HIV-1), these immune cell interactions can also promote the spread of the virus within the host. The main target of HIV-1 infection is the CD4⁺ helper T lymphocyte, a cell type that is responsible for coordinating immune responses and modulating effector responses to foreign antigens. As part of their normal immune surveillance duties, these cells migrate actively within lymphoid tissues and can travel from inductive sites to effector sites in search of their cognate antigen. For CD4⁺ T cells, there is an ongoing search for a unique peptide antigen presented in the context of class II MHC that can activate a proliferative or tolerogenic response. This iterative and continual probing and interrogation of other cells determine the outcome of immune responses. Recent studies in vitro have revealed that the viral infection program induces cell–cell interactions called virological synapses between infected and uninfected CD4⁺ T cells. These long-lived, virally induced adhesive contacts greatly enhance the rate of productive infection and may be central to the spread of the virus in vivo. Here, we review aspects of this efficient mode of cell-to-cell infection and the implications for our understanding of HIV-1 pathogenesis.     

T cell immunity to SARS-CoV-2

Exceptional efforts have been undertaken to shed light into the biology of adaptive immune responses to SARS-CoV-2. T cells occupy a central role in adaptive immunity to mediate helper functions to different arms of the immune system and are fundamental to mediate protection, control, and clearance of most viral infections. Even though many questions remain unsolved, there is a growing literature linking specific T cell characteristics to differential COVID-19 severity and vaccine outcome. In this review, we summarize our current understanding of CD4⁺ and CD8⁺ T cell responses in acute and convalescent COVID-19. Further, we discuss the T cell literature coupled to pre-existing immunity and vaccines and highlight the need to look beyond blood to fully understand how T cells function in the tissue space.     

Loss of HIV-specific memory B-cells as a potential mechanism for the dysfunction of the humoral immune response against HIV

A central, yet unresolved issue in the pathogenesis of HIV disease is the mechanism of antibody perturbation. In this study, HIV-specific memory B-cells were quantified in groups of infected subjects and compared with memory responses to other antigens and antibody titers. HIV-specific memory B-cell responses were vigorous in individuals with CD4⁺ T-cell counts > 350/μl and weak or undetectable in subjects with CD4⁺ T-cell numbers < 200/μl. Memory B-cell loss was permanent, because antiretroviral therapy failed to restore HIV-specific memory responses while influenza- and tetanus toxoid-specific memory B-cells remained unaffected or recovered. Antibody titers to Gag strongly correlated with memory B-cell frequencies. In contrast, Env-specific antibodies were maintained in advanced disease despite low or undetectable levels of memory B-cells. These results provide a potential mechanism by which destruction of HIV-specific CD4⁺ T-cells affects the humoral immune response against HIV and compromises the ability to maintain an effective antibody response.     

Where the Wild Things Are: Pathogenesis of SIV Infection in African Nonhuman Primate Hosts

African nonhuman primates that are natural hosts of simian immunodeficiency virus (SIV) are generally spared from disease progression. Pathogenic and nonpathogenic SIV infections share some major features: high viral replication, massive acute depletion of mucosal CD4⁺ T cells, and partial control of the virus by both adaptive and innate immune responses. A key distinction of natural SIV infections is rapid and active control of immune activation and apoptosis of T cells that contributes to the integrity of mucosal barrier and lack of microbial translocation. This allows partial recovery of CD4⁺ T cells and preservation of the function of other immune cell subsets. A better understanding of the mechanisms underlying the lack of disease in natural hosts for SIV infection will likely provide important clues as to the therapy of HIV-1 infection.     

T cell functionality in HIV-1, HIV-2 and dually infected individuals: correlates of disease progression and immune restoration

The role of suppressive anti-retroviral therapy (ART) in eliciting restoration of dysregulated immune function remains unclear in HIV-1 infection. Also, due to tailoring of therapeutic regimens towards HIV-1, this possible impairment of therapy may be even more pronounced in HIV-2 and dual (HIV-D) infection. Thus, we evaluated the impact of ART on immune restoration by assessing T cell functions, including HIV specific responses in HIV-1-, HIV-2- and HIV-D-infected individuals. Both ART-treated and naive infected subjects showed persistently altered frequency of CD4⁺ T cell subsets [regulatory T cells (T_reg), naive/central memory, effector memory], increased immune activation, cytoxicity and decreased frequency of natural killer T (NKT)- like cells and T helper type 17 (Th17)/T_reg ratio with elevated microbial translocation. Further, HIV-specific responses were dominated by gag-specific CD4⁺ T cells in virologically suppressed HIV-D individuals, suggesting retention of T cell memory for both viruses. Increased antigen-specific responses, including dual-functional interleukin (IL)-2/interferon (IFN)-γ CD4⁺ T cells, were detected in therapy receiving HIV-2-infected individuals indicative of a greater and more functionally diverse T cell memory repertoire. We delineated immune signatures specific to therapy-naive single HIV infection, as well as a unique signature associated with HIV-2 disease progression and immune restoration. Circulating T_reg frequency, T cell activation and microbial translocation levels correlated with disease progression and immune restoration among all types of HIV infection. Also, memory responses negatively correlated, irrespective of type of infection, in ART receiving infected individuals, with CD4 rebound and decreased pan T cell activation. Our data highlight the need for adjunct immunomodulatory therapeutic strategies to achieve optimal immune restoration in HIV infection.     

Cytotoxic HIV-1 p55gag-specific CD4+ T cells produce HIV-inhibitory cytokines and chemokines

CD4⁺ T-helper cells appear to be essential in sustaining immune responses in chronic viral infections, as the maintenance of CD8⁺ cytotoxic T-lymphocyte responses and the control of viremia were demonstrated to depend on CD4⁺ T cell help. In order to investigate the function of HIV-specific CD4⁺ T cells in chronic HIV-1-infection, 49 chronically HIV-infected patients were analyzed before and 3 and 6 months after initiation of antiviral treatment. Ten patients showed a substantial, although weak, proliferative response to HIV-1-p55^gag protein for which no improvement was observed upon initiation of HAART. From one individual, HIV-1-p55^gag-specific CD4-positive T-cell clones were generated that were heterogeneous in their TCR V gene usage and HLA-DRB1*13 and DRB1*03 restricted, respectively. In addition, some CD4⁺ TCC produced substantial amounts of IFN- and MIP-1/, were perforin-positive, and showed cytotoxic activity. These diverse functional features of HIV-specific CD4⁺ T cells suggest that they may exert direct antiviral activity.