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The forkhead box P1 (FOXP1) transcription factor has been shown to regulate the generation and maintenance of quiescent naïve murine T cells. In humans, FOXP1 expression has been correlated with overall survival in patients with peripheral T-cell lymphoma (PTCL), although its regulatory role in T-cell function is currently unknown. We found that FOXP1 is normally expressed in all human leukocyte subpopulations. Eur. J. Immunol. 2017. 47: 168-179 Immunomodulation and immune therapies 169 IntroductionCellular quiescence defines cell cycle arrest in the G0 phase, which is characterized by lower rates of transcription, translation, and metabolism thereby reducing the consumption of nutrients required to maintain cellular activities. This reversible state may indirectly deter malignant transformation by protecting cells from metabolic damage. In lymphocytes, quiescence is distinct from anergy and senescence and can be reversed by antigenic stimulation. Initially, quiescence was thought to result from the absence of activating signals, but growing evidence from murine models and in vitro cell line studies reveals that quiescence is actively controlled by a transcriptional program [1]. Several transcription factors (TF) have been shown to play a role in T-cell quiescence, including LKLF, a zinc finger TF and TOB1, an anti-proliferative TF [2,3]. Expression levels of these transcriptional regulators are high in naïve T cells and decrease dramatically following TCR crosslinking. Their suppression decreases the T-cell activation threshold, resulting in increased T-cell proliferation and effector functions. Murine studies have shown that a forkhead box (FOX) TF, FOXP1, is essential for the generation of quiescent naïve T cells during thymocyte development and maintaining quiescence in the periphery [4,5].The FOX TF family performs diverse functions, including regulating development and organogenesis, metabolism, and immune responses. FOX TF are identified by a conserved 110-amino acid DNA-binding (winged helix) domain [6,7]. Members of the FOXP subfamily, including FOXP1-FOXP4, contain a zinc finger domain and a leucine zipper motif and form homo-or heterodimers [8]. In the murine immune system, FOXP1 acts as an essential transcriptional regulator of B-cell lymphopoiesis by directly regulating the B-cell specific Erag enhancer [9]. Moreover, its downregulation is required for B-cell transit through the germinal center (GC) [10]. FOXP1 is also expressed in monocytes and has been shown to regulate their differentiation both in human cell lines and in a murine model where it was also shown to control macrophage functions [11,12]. A recent study demonstrated that upregulation of FOXP1 in CD8 + T cells drives T-cell unresponsiveness in cancer by blocking proliferation and major T cell functions, including degranulation of cytotoxic granules and cytokine release. This state, which is distinct from anergy and exhaustion, involves FOXP1 and Smad2/Smad3 interactions, both translocated to the nucleus in response to TGF-β signalin...

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Tertiary lymphoid structures (TLS) have been detected in several types of human solid tumors. These structures are thought to regulate local adaptive immune responses that can promote or antagonize tumor progression. Despite positive prognostic values associated with a TLS presence in several studies, discrepancies still exist. TLS are structurally organized entities composed of varying numbers of multiple cell types making their assessment in tumor tissues, particularly biopsies, challenging. Immunohistochemical staining of TLS-related cell populations is the most frequently used method for identifying and scoring them; however, TLS-related gene expression has also been explored. The protocols described are detailed to allow the user to quantify TLS-related gene expression on formalin-fixed paraffin-embedded human breast tumor tissues.