Dual CD47 and PD-L1 blockade elicits anti-tumor immunity by intratumoral CD8 T cells.

Objectives: Bispecific antibodies targeting CD47 and PD-L1 (CD47 × PD-L1 BisAb) demonstrate efficacy against a range of solid cancers. While dual blockade negates anti-CD47-mediated toxicity, the effect of combined innate and adaptive immune activation on protective tumor-resident CD8 T cells has yet to be fully elucidated.

Methods: CD8 T cell populations were tracked upon CD47 × PD-L1 BisAb treatment in an orthotopic model of murine breast cancer where anti-tumor immunity is mediated by CD8 T cells.

Lack of B Lymphocytes Enhances CD8 T Cell-Mediated Resistance against Respiratory Viral Infection but Compromises Memory Cell Formation.

Following a respiratory virus infection, CXCR3 CX3CR1 and CXCR3 CX3CR1 CD8 T cells localize to different compartments within the lung and play an important role in host resistance, but mechanisms governing their optimal generation are poorly defined. We serendipitously found that B cell-deficient (μMT) mice were highly resistant to lethal infection with a virulent poxvirus strain and that depletion of CD8 T cells rendered these mice susceptible to infection. B cells were not required for the expansion of virus-specific CD8 T cells, but a greater proportion of activated CD8 T cells acquired an effector-like CXCR3 CX3CR1 phenotype in the absence of B cells.

Batf3-Dependent Dendritic Cells Promote Optimal CD8 T Cell Responses against Respiratory Poxvirus Infection.

Respiratory infection with vaccinia virus (VacV) elicits robust CD8 T cell responses that play an important role in host resistance. In the lung, VacV encounters multiple tissue-resident antigen-presenting cell (APC) populations, but which cell plays a dominant role in priming of virus-specific CD8 effector T cell responses remains poorly defined. We used Batf3 mice to investigate the impact of CD103 and CD8α dendritic cell (DC) deficiency on anti-VacV CD8 T cell responses.

The TNF Superfamily Molecule LIGHT Promotes the Generation of Circulating and Lung-Resident Memory CD8 T Cells following an Acute Respiratory Virus Infection.

The transition of effector T cells or memory precursors into distinct long-lived memory T cell subsets is not well understood. Although many molecules made by APCs can contribute to clonal expansion and effector cell differentiation, it is not clear if clonal contraction and memory development is passive or active. Using respiratory virus infection, we found that CD8 T cells that cannot express the TNF family molecule lymphotoxin-like, exhibits nducible expression, competes with HSV lycoprotein D for herpes virus entry mediator, a receptor expressed by T lymphocytes (LIGHT) are unimpaired in their initial response and clonally expand to form effector cell pools.

Inflammatory monocytes contribute to the persistence of CXCR3 CX3CR1 circulating and lung-resident memory CD8 T cells following respiratory virus infection.

Phenotypically diverse memory CD8 T cells are present in the lungs that either re-circulate or reside within the tissue. Understanding the key cellular interactions that regulate the generation and then persistence of these different subsets is of great interest. Recently, DNGR-1 dendritic cell (DC) mediated priming was reported to control the generation of lung-resident but not circulating memory cells following respiratory viral infection.

HVEM Imprints Memory Potential on Effector CD8 T Cells Required for Protective Mucosal Immunity.

Mucosal immunity to reinfection with a highly virulent virus requires the accumulation and persistence of memory CD8 T cells at the site of primary infection. These cells may derive from memory precursor effector cells (MPECs), which are distinct from short-lived effector cells that provide acute protection but are often destined to die. Using respiratory virus infection, we show that herpes virus entry mediator (HVEM; TNFRSF14), a member of the TNF receptor superfamily, provides key signals for MPEC persistence.

Tissue-specific programming of memory CD8 T cell subsets impacts protection against lethal respiratory virus infection.

How tissue-specific anatomical distribution and phenotypic specialization are linked to protective efficacy of memory T cells against reinfection is unclear. Here, we show that lung environmental cues program recently recruited central-like memory cells with migratory potentials for their tissue-specific functions during lethal respiratory virus infection. After entering the lung, some central-like cells retain their original CD27CXCR3 phenotype, enabling them to localize near the infected bronchiolar epithelium and airway lumen to function as the first line of defense against pathogen encounter.

Transcription Factor Bcl11b Controls Effector and Memory CD8 T cell Fate Decision and Function during Poxvirus Infection.

CD8 T cells play an important role in host resistance to many viral infections, but the underlying transcriptional mechanisms governing their differentiation and functionality remain poorly defined. By using a highly virulent systemic and respiratory poxvirus infection in mice, we show that the transcription factor Bcl11b provides a dual trigger that sustains the clonal expansion of virus-specific effector CD8 T cells, while simultaneously suppressing the expression of surface markers associated with short-lived effector cell (SLEC) differentiation. Additionally, we demonstrate that Bcl11b supports the acquisition of memory precursor effector cell (MPEC) phenotype and, thus, its absence causes near complete loss of lymphoid and lung-resident memory cells.