Defining T Cell Tissue Residency in Humans: Implications for HIV Pathogenesis and Vaccine Design.

Purpose of review:This review summarizes recent literature defining tissue-resident memory T cells (TRM) and discusses implications for HIV pathogenesis, vaccines, and eradication efforts.Recent findings:Investigations using animal models and human tissues have identified a TRM transcriptional profile and elucidated signals within the tissue microenvironment leading to TRM development and maintenance. TRM are major contributors to host response in infectious diseases and cancer; in addition, TRM contribute to pathogenic inflammation in a variety of settings. Although TRM are daunting to study in HIV infection, recent work has helped define their molecular signatures and effector functions and tested strategies for their mobilization. Exclusive reliance on blood sampling to gain an understanding of host immunity overlooks the contribution of TRM, which differ in significant ways from their counterparts in circulation. It is hoped that greater understanding of these cells will lead to novel approaches to prevent and/or eradicate HIV infection

THE SCIENCE OF CONNECTIVENESS PART II: MAPPING BEYOND SPACE-TIME

This is the second in a series of three articles that will outline a proposed scientific model with the goal of stimulating a new vision toward resolving the Mind-matter question and acknowledging an underlying connectiveness in the universe. Scientific is understood to mean that the "parts" or links already exist as useful concepts in the scientific community. The model being proposed assumes that everyday reality is not simply "out there" nor is it "within." Rather, it is suggested that everyday reality is a "perception" we construct from aspects of the "unity" within which we are immersed. Parr I presented the basic assumptions of the model and introduced the model by exploring aspects of a reality that extends beyond our limited concepts of three dimensional space plus time. 1•2 The power of symbolic patterns in the physical for serving the role of mediator between the happenings in the physical (or outer reality) and the menral (or inner reality) was emphasized. Part II, Mapping Beyond Space-Time, discusses a process of interfacing between Mind and matter consistenr with the concepts of quantum physics. Emphasis is placed upon the quantum feature of non-locality and upon twistor theory. The issues of causality and reproducibility in science are discussed. The article concludes with a description of the dynamics of the process-how the interplay takes place and works. This includes an outline of other symbolic tools of mathematics such as chaos theory that permit extending out three dimensional thinking. In Part III the authors will explore [he relationship of their model to human experience

THE SCIENCE OF CONNECTIVENESS PART III: THE HUMAN EXPERIENCE

This is the third in a series of three articles that outline a proposed scientific model with the goal of stimulating a new vision-one that acknowledges an underlying connectiveness in the universe. Part I: "Modeling A Greater Unity" and Part II: "Mapping Beyond Space-Time" were published in the two preceding issues of Subtle Energies. Part III, "The Human Experience" will summarize the model, address possible mechanisms underlying the emergence of space and time, describe the physically measurable connections ro the human from beyond space-time, and relate this process to our perception of reality. This series of three articles on the model and the supporting evidence has presented an alternative way to think about phenomena at the human leveL The expanded science outlined could well lead to a world view or paradigm that will help us better understand how we perceive "reality." The interplay between the body/heart/brain and patterns beyond space-time and the relationship of this interplay to the set of real physical constraints that govern the electrochemistry of the body becomes apparent. The model provides a physical basis for understanding why there can be no actual limits to human potential

Predominance of weakly cytotoxic, T-betLowEomesNeg CD8+ T-cells in human gastrointestinal mucosa: implications for HIV infection.

The gastrointestinal mucosa is an important site of HIV acquisition, viral replication, and pathogenesis. Immune cells in mucosal tissues frequently differ in phenotype and function from their non-mucosal counterparts. Although perforin-mediated cytotoxicity as measured in blood is a recognized correlate of HIV immune control, its role in gastrointestinal tissues is unknown. We sought to elucidate the cytotoxic features of rectal mucosal CD8+ T-cells in HIV infected and uninfected subjects. Perforin expression and lytic capacity were significantly reduced in rectal CD8+ T-cells compared with their blood counterparts, regardless of HIV clinical status; granzyme B (GrzB) was reduced to a lesser extent. Mucosal perforin and GrzB expression were higher in participants not on antiretroviral therapy compared with those on therapy and controls. Reduction in perforin and GrzB was not explained by differences in memory/effector subsets. Expression of T-bet and Eomesodermin was significantly lower in gut CD8+ T-cells compared with blood, and in vitro neutralization of TGF-β partially restored perforin expression in gut CD8+ T-cells. These findings suggest that rectal CD8+ T-cells are primarily non-cytotoxic, and phenotypically shaped by the tissue microenvironment. Further elucidation of rectal immune responses to HIV will inform the development of vaccines and immunotherapies targeted to mucosal tissues

Dynamic MAIT cell response with progressively enhanced innateness during acute HIV-1 infection.

Mucosa-associated invariant T (MAIT) cell loss in chronic HIV-1 infection is a significant insult to antimicrobial immune defenses. Here we investigate the response of MAIT cells during acute HIV-1 infection utilizing the RV217 cohort with paired longitudinal pre- and post-infection samples. MAIT cells are activated and expand in blood and mucosa coincident with peak HIV-1 viremia, in a manner associated with emerging microbial translocation. This is followed by a phase with elevated function as viral replication is controlled to a set-point level, and later by their functional decline at the onset of chronic infection. Interestingly, enhanced innate-like pathways and characteristics develop progressively in MAIT cells during infection, in parallel with TCR repertoire alterations. These findings delineate the dynamic MAIT cell response to acute HIV-1 infection, and show how the MAIT compartment initially responds and expands with enhanced function, followed by progressive reprogramming away from TCR-dependent antibacterial responses towards innate-like functionality