Microbiota-Specific Foxp3+ Regulatory T Cells Could Control Pathological T Helper Responses.

Upon engaging cognate peptide MHC-II complexes (pMHC-IIs), naive CD4+ T cells differentiate and acquire several T helper (Th) fates, guided by a dynamic cytokine milieu following antigenic challenge. This physiological Th fate choice process is often erroneously conflated with a maladaptive pathological process historically termed Th polarization. Here we propose why these two processes are distinct and separable. We posit that, though innate signaling alone is sufficient for Th fate choice in naive CD4+ T cells, Th polarization instead strictly originates from pre-existing cross-reactive memory CD4+ T cells. We further posit that Th polarization is normally prevented by thymus-derived cross-reactive antigen-specific regulatory T cells (Tregs) and inevitably manifests as immunopathology when the Treg repertoire and the microbiota that maintains it are selectively depleted. Bifurcating Th fate choice and polarization delineate Th effector pathways more accurately and tangibly improve the scope of targeted therapies for allergies, autoimmune diseases, and effective vaccines.

Could cross-reactivity rescue Foxp3+ regulatory T cell precursors from thymic deletion?

Thymocytes that bind with high affinity to peptides displayed by MHC class II (pMHC-II) are deleted while low-affinity binders differentiate into naive CD4+ T cells. However, Foxp3+ regulatory T cells (Tregs) seem to defy this binary choice as their precursors require high-affinity interaction with pMHC-II for maturation in the thymus. Here, we rely on the antigen-specific interpretive framework, SPIRAL (Specific ImmunoRegulatory Algorithm), to propose that Tregs escape thymic deletion by forming dyads with IL-2-producing T cells via antigen cross-reactivity. This interpretation reconciles contradictions related to Treg ontogeny in the thymus and their role in modulating antigen-specific immune responses.

Concurrent cross-reactivity of microbiota-derived epitopes to both self and pathogens may underlie the "Hygiene hypothesis".

The current iteration of the "Hygiene hypothesis" proposes precipitous decline in exposure to conserved microbial products and metabolites in individuals in developed countries undermines innate self-nonself "training" of immune system leading to allergy and autoimmunity. However, lack of innate "training" alone fails to account for the antigen-driven nature of these immunopathologies. Here, we advance an alternative, antigen-specific interpretive framework, SPIRAL (Specific ImmunoRegulatory Algorithm) that predicts "loss" of commensal microbiota-derived epitopes cross-reactive to both self and pathogens, rather than conserved microbial moieties or metabolites, underlies the "Hygiene hypothesis." By mechanistically delineating how loss of selective microbiota in predisposed individuals could lead to corresponding "holes" in the epitope-specific Foxp3+ regulatory T cell repertoire and subsequent selective immunopathologies, SPIRAL represents a novel interpretation of cross-reactivity that could enable targeted discovery of microbiota species and their associated Treg epitopes "missing" in the diseases "Hygiene hypothesis" implicates, and provides a roadmap for a novel unified interpretation of self-nonself discrimination and T helper phenotype selection.

Tissue-based class control: the other side of tolerance.

In this Essay, we offer a new perspective on how immune responses are regulated. We do not cover how they are turned on and off, but focus instead on the second major aspect of an immune response: the control of effector class. Although it is generally thought that the class of an immune response is tailored to fit the invading pathogen, we suggest here that it is primarily tailored to fit the tissue in which the response occurs. To this end, we cover such topics as the nature of T helper (T(H)) cell subsets (current and yet to be discovered), the nature of privileged sites, the difference between oral tolerance and oral vaccination, why the route of immunization matters, whether the T(H)1-type response is really the immune system's primary defense, and whether there might be a different role for some regulatory T cells.

Protective response to Leishmania major in BALB/c mice requires antigen processing in the absence of DM.

Protection from the parasite Leishmania major is mediated by CD4 T cells. BALB/c mice are susceptible to L. major and show a nonprotective immunodominant CD4 T cell response to Leishmania homolog of activated receptor for c-kinase (LACK) 158-173. Host genes that underlie BALB/c susceptibility to L. major infections are poorly defined. DM, a nonclassical MHC class II molecule, due to its peptide editing properties has been shown to 1) edit the repertoire of peptides displayed by APC, and 2) focus the display of epitopes by APC to the immunodominant ones. We tested the hypothesis that deficiency of DM, by causing presentation of a different array of epitopes by infected APC than that presented by DM-sufficient APC, may change the course of L. major infection in the susceptible BALB/c mice. We show herein that unlike their susceptible wild-type counterparts, BALB/c mice deficient in DM are protected from infections with L. major. Furthermore, DM-deficient mice fail to display the immunodominant LACK 158-173 on infected APC. In its place, infected DM(-/-) hosts show elicitation of CD4 T cells specific for newer epitopes not presented by wild-type L. major-infected APC. Protection of BALB/c DM(-/-) mice is dependent on IFN-gamma. DM is thus a host susceptibility gene in BALB/c mice, and Ag processing in the absence of DM results in elicitation of a protective T cell response against L. major infections. This report suggests a novel mechanism to trigger host resistance against pathogens.

The MHC class II-associated invariant chain interacts with the neonatal Fc gamma receptor and modulates its trafficking to endosomal/lysosomal compartments.

The neonatal Fc receptor for IgG (FcRn) transfers maternal IgG to the offspring and protects IgG from degradation. The FcRn resides in an acidic intracellular compartment, allowing it to bind IgG. In this study, we found the association of FcRn and invariant chain (Ii). The interaction was initiated within the endoplasmic reticulum by Ii binding to either the FcRn H chain alone or FcRn H chain-beta(2)-microglobulin complex and appeared to be maintained throughout the endocytic pathway. The CLIP in Ii was not required for FcRn-Ii association. The interaction was also detected in IFN-gamma-treated THP-1, epithelial and endothelial cells, and immature mouse DCs. A truncated FcRn without the cytoplasmic tail was unable to traffic to early endosomes; however, its location in early endosomes was restored by Ii expression. FcRn was also detected in the late endosome/lysosome only in the presence of Ii or on exposure to IFN-gamma. In immature human or mouse DCs, FcRn was barely detected in the late endosome/lysosome in the absence of Ii. Furthermore, the cytoplasmic tail of Ii conferred tailless FcRn to route to both the early endosome and late endosome/lysosome in a hybrid molecule. Because the FcRn is expressed in macrophages and DCs or epithelial and endothelial cells where Ii is induced under inflammation and infection, these results reveal the complexity of FcRn trafficking in which Ii is capable of expanding the boundary of FcRn trafficking. Taken together, the intracellular trafficking of FcRn is regulated by its intrinsic sorting information and/or an interaction with Ii chain.

Brief antigenic stimulation generates effector CD8 T cells with low cytotoxic activity and high IL-2 production.

It is currently believed that a brief antigenic stimulation is sufficient to induce CD8 T cells to complete their differentiation program, become effector T cells, and subsequently generate memory. Because this concept was derived from studies in which only a single effector function was analyzed (either IFN-gamma production or target cell lysis), we wondered whether monitoring for multiple effector functions might reveal novel characteristics of effector CD8 T cells elicited by brief or prolonged Ag exposure. Using an in vitro system to generate effector T cells and an in vivo adoptive transfer model to track donor CD8 T cells, we found that the differentiation programs acquired by CD8 T cells after brief or prolonged antigenic stimulation were different. Although the frequencies of IFN-gamma and TNF-alpha producers were comparable for both effector CD8 T cell populations, there were major differences in cytotoxic potential and IL-2 production. Whereas prolonged (>24 h) Ag exposure stimulated effector CD8 T cells with high cytotoxic activity and low IL-2 production, brief (<24 h) stimulation generated effector CD8 T cells with low cytotoxic activity and high IL-2 production. The latter effector T cells rapidly converted into central memory-like CD8 T cells, exhibited long-term survival in adoptively transferred hosts, and gave robust recall responses upon Ag challenge. These data suggest that not all functions of effector CD8 T cells are equally inherited after brief or prolonged antigenic stimulation.