Farhad Dastmalchi

Protein tyrosine phosphatase PTPN22 has dual roles in promoting pathogen versus homeostatic-driven CD8 T-cell responses

PTPN22 (protein tyrosine phosphatase non receptor 22) encodes a tyrosine phosphatase that functions as a key regulator of immune homeostasis. In particular, PTPN22 inhibits T‐cell receptor signaling and selectively promotes type I interferon responses in myeloid cells. To date, there is little information on the CD8 T‐cell‐intrinsic role of PTPN22 in response to a viral pathogen. We unexpectedly found that PTPN22‐deficient virus‐specific CD8 T cells failed to accumulate in wild‐type hosts after lymphocytic choriomeningitis virus infection. Lack of PTPN22 expression altered CD8 T‐cell activation and antiviral cytokine production, but did not significantly affect the composition of effector and memory cell precursors. Most significantly, in vivo, PTPN22‐deficient CD8 T cells showed a profound defect in upregulating STAT‐1 after lymphocytic choriomeningitis virus infection and considerably less phosphorylation of STAT‐1 in response to IFN‐α treatment in vitro compared with their wild‐type counterparts. In stark contrast, following transfer into lymphopenic mice, CD8 T‐cell expansion and central‐like phenotype, was considerably increased in the absence of PTPN22. Collectively, our results suggest that PTPN22 has dual roles in T‐cell clonal expansion and effector function; whereas it promotes antigen‐driven responses during acute infection by positively regulating interferon signaling in T cells, PTPN22 inhibits homeostatic‐driven proliferation.

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 inducible expression, competes with HSV glycoprotein 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. Thereafter, LIGHT-deficient CD8 T cells undergo strikingly enhanced clonal contraction with resultant compromised accumulation of both circulating and tissue-resident memory cells. LIGHT expression at the peak of the effector response regulates the balance of several pro- and antiapoptotic genes, including Akt, and has a preferential impact on the development of the peripheral memory population. These results underscore the importance of LIGHT activity in programming memory CD8 T cell development, and suggest that CD8 effector T cells can dictate their own fate into becoming memory cells by expressing LIGHT.

Temozolomide for immunomodulation in the treatment of glioblastoma

Temozolomide is the most widely used chemotherapy for patients with glioblastoma (GBM) despite the fact that approximately half of treated patients have temozolomide resistance and all patients eventually fail therapy. Due to the limited efficacy of existing therapies, immunotherapy is being widely investigated for patients with GBM. However, initial immunotherapy trials in GBM patients have had disappointing results as monotherapy. Therefore, combinatorial treatment strategies are being investigated. Temozolomide has several effects on the immune system that are dependent on mode of delivery and the dosing strategy, which may have unpredicted effects on immunotherapy. Here we summarize the immune modulating role of temozolomide alone and in combination with immunotherapies such as dendritic cell vaccines, T-cell therapy, and immune checkpoint inhibitors for patients with GBM.