Affinity maturation of antibody responses is mediated by differential plasma cell proliferation.

Increased antibody affinity over time after vaccination, known as affinity maturation, is a prototypical feature of immune responses. Recent studies have shown that a diverse collection of B cells, producing antibodies with a wide spectrum of different affinities, are selected into the plasma cell (PC) pathway. How affinity-permissive selection enables PC affinity maturation remains unknown.

Affinity maturation of antibody responses is mediated by differential plasma cell proliferation.

Increased antibody affinity over time after vaccination, known as affinity maturation, is a prototypical feature of immune responses. Recent studies have shown that a diverse collection of B cells, producing antibodies with a wide spectrum of different affinities, are selected into the plasma cell (PC) pathway. How affinity-permissive selection enables PC affinity maturation remains unknown.

Role of affinity in plasma cell development in the germinal center light zone.

Protective immune responses to many pathogens depend on the development of high-affinity antibody-producing plasma cells (PC) in germinal centers (GCs). Transgenic models suggest that there is a stringent affinity-based barrier to PC development. Whether a similar high-affinity barrier regulates PC development under physiologic circumstances and the nature of the PC fate decision has not been defined precisely.

Memory B cell development elicited by mRNA booster vaccinations in the elderly.

Despite mRNA vaccination, elderly individuals remain especially vulnerable to severe consequences of SARS-CoV-2 infection. Here, we compare the memory B cell responses in a cohort of elderly and younger individuals who received mRNA booster vaccinations. Plasma neutralizing potency and breadth were similar between the two groups.

Continuous germinal center invasion contributes to the diversity of the immune response.

Antibody responses are characterized by increasing affinity and diversity over time. Affinity maturation occurs in germinal centers by a mechanism that involves repeated cycles of somatic mutation and selection. How antibody responses diversify while also undergoing affinity maturation is not as well understood.

Germinal center-dependent and -independent memory B cells produced throughout the immune response.

Memory B cells comprise a heterogenous group of cells that differ in origin and phenotype. During the early phases of the immune response, activated B cells can differentiate into IgM-expressing memory cells, short-lived plasma cells, or seed germinal centers (GCs). The memory compartment is subsequently enriched by B cells that have been through several rounds of division and selection in the GC.

VISTA: A Target to Manage the Innate Cytokine Storm.

In recent years, the success of immunotherapy targeting immunoregulatory receptors (immune checkpoints) in cancer have generated enthusiastic support to target these receptors in a wide range of other immune related diseases. While the overwhelming focus has been on blockade of these inhibitory pathways to augment immunity, agonistic triggering these receptors offers the promise of dampening pathogenic inflammatory responses. V-domain Ig suppressor of T cell activation (VISTA) has emerged as an immunoregulatory receptor with constitutive expression on both the T cell and myeloid compartments, and whose agonistic targeting has proven a unique avenue relative to other checkpoint pathways to suppress pathologies mediated by the innate arm of the immune system.

VISTA Re-programs Macrophage Biology Through the Combined Regulation of Tolerance and Anti-inflammatory Pathways.

We present the novel finding that V-domain Ig suppressor of T cell activation (VISTA) negatively regulates innate inflammation through the transcriptional and epigenetic re-programming of macrophages. Representative of VISTA re-programming is the ability of VISTA agonistic antibodies to augment LPS tolerance and reduce septic shock lethality in mice. This anti-inflammatory effect of anti-VISTA was mimicked demonstrating that anti-VISTA treatment caused a significant reduction in LPS-induced IL-12p40, IL-6, CXCL2, and TNF; all hallmark pro-inflammatory mediators of endotoxin shock.

Rethinking peripheral T cell tolerance: checkpoints across a T cell's journey.

Following their exit from the thymus, T cells are endowed with potent effector functions but must spare host tissue from harm. The fate of these cells is dictated by a series of checkpoints that regulate the quality and magnitude of T cell-mediated immunity, known as tolerance checkpoints. In this Perspective, we discuss the mediators and networks that control the six main peripheral tolerance checkpoints throughout the life of a T cell: quiescence, ignorance, anergy, exhaustion, senescence and death.

CDDO-Me Alters the Tumor Microenvironment in Estrogen Receptor Negative Breast Cancer.

The tumor microenvironment (TME) is an essential contributor to the development and progression of malignancy. Within the TME, tumor associated macrophages (TAMs) mediate angiogenesis, metastasis, and immunosuppression, which inhibits infiltration of tumor-specific cytotoxic CD8+ T cells. In previous work, we demonstrated that the synthetic triterpenoid CDDO-methyl ester (CDDO-Me) converts breast TAMs from a tumor-promoting to a tumor-inhibiting activation state in vitro.

VISTA is a checkpoint regulator for naïve T cell quiescence and peripheral tolerance.

Negative checkpoint regulators (NCRs) temper the T cell immune response to self-antigens and limit the development of autoimmunity. Unlike all other NCRs that are expressed on activated T lymphocytes, V-type immunoglobulin domain-containing suppressor of T cell activation (VISTA) is expressed on naïve T cells. We report an unexpected heterogeneity within the naïve T cell compartment in mice, where loss of VISTA disrupted the major quiescent naïve T cell subset and enhanced self-reactivity.

Defining the Signature of VISTA on Myeloid Cell Chemokine Responsiveness.

The role of negative checkpoint regulators (NCRs) in human health and disease cannot be overstated. V-domain Ig-containing Suppressor of T-cell Activation (VISTA) is an Ig superfamily protein predominantly expressed within the hematopoietic compartment and has been studied for its role in the negative regulation of T cell responses. The findings presented in this study show that, unlike all other NCRs, VISTA deficiency dramatically impacts on macrophage cytokine and chemokine production, as well as the chemotactic response of VISTA-deficient macrophages.

VISTA: a novel immunotherapy target for normalizing innate and adaptive immunity.

V-domain Ig suppressor of T cell activation (VISTA) is a novel checkpoint regulator with limited homology to other B7 family members. The constitutive expression of VISTA on both the myeloid and T lymphocyte lineages coupled to its important role in regulating innate and adaptive immune responses, qualifies VISTA to be a promising target for immunotherapeutic intervention. Studies have shown differential impact of agonistic and antagonistic targeting of VISTA, providing a unique landscape for influencing the outcome of cancer and inflammatory diseases.