Update research.md

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@@ -13,8 +13,8 @@ T cells drive immune activation and promote clearance of infections and cancer.
 
 The clinical efficacy of cancer immunotherapies targeting the immune ‘checkpoints’ PD-1 and CTLA-4 provides powerful evidence of the therapeutic relevance of immunoregulatory mechainsms. Such therapies have revolutionised the treatment of patients with a variety of advanced cancers, including metastatic melanoma. However, these therapies, which are thought to work primarily by affecting CD8+ T cells, are ineffective at inducing durable responses in a majority of patients and a majority of cancer types, identifying a pressing need to discover new and mechanistically distinct immunoregulatory mechanisms to drive advances in cancer and inflammatory disease immunotherapy. 
 
-## Research themes
-### Mechanisms of regulatory T (Treg) cell development and function
+### Research themes
+#### Mechanisms of regulatory T (Treg) cell development and function
 
 **Regulatory T (Treg) cells** are rare immune cells with powerful suppressive functions. Loss of Treg cells results in lethal inflammation, while defects in their function are associated with autoimmunity and allergy. Treg cells also suppress immune responses in cancer. There is intense medical interest in exploiting the powerful biological functions of Treg cells to treat patients with inflammatory diseases, transplantation and cancer. However, most efforts have thusfar been disappointing. We aim to better define mechanisms of Treg development and function, to identify new ways of exploiting or blocking the suppressive function of Treg cells in individuals with inflammation and cancer (**Fig. 1**).  
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@@ -27,7 +27,7 @@ The immunoregulatory function of Treg cells is a major focus of the laboratory's
 
 Our group showed that a distal enhancer at the prominent human autoimmune/allergic disease risk locus at chromosome 11q13.5 restricts gut inflammation by promoting expression of the TGF-b docking receptor GARP on Treg cells, revealing a novel mechanism of immune regulation in the gut (Nature 2020).  We have shown that Treg differentiation is sensitive to local oxygen concentration contributing to lung immune homeostasis but creating a permissive environment for pulmonary cancer metastasis (Cell 2016). We showed that CCR8 expression marks Treg cells with highly suppressive function in tumours but that it is dispensable for their accumulation and suppressive function (Immunology 2021). 
 
-### T cell maintenance and memory
+#### T cell maintenance and memory
 T cell responses are clonally expanded from small numbers of antigen-specific naive precursor cells which arose during thymic development. Upon priming, antigen-specific T cell responses must be maintained over long periods of time to enable T cell memory and durable responses to chronic antigens. Our laboratory is interested in the mechanisms that underpin long-lived T cell responses.
 
 **CD8+ T cell memory** has been the focus of our prior research. However, we have recently become interested in understanding how clonal Treg responses are maintained over time. To work properly, Treg responses need to be remarkably long-lived: Treg cells produced during a critical time-window in early life need to be maintained throughout life to prevent lethal inflammation. Treg populations are maintained despite reduced thymic output of T cells as we age, and in the definitive absence of thymic output. The transfer of mature Treg cells into Treg-deficient mice establishes a long-lived population that prevents lethal inflammation over the lifespan of the host. **Maintenance of Treg responses** is also critical to immunoregulatory memory, limiting harmful immune reactions upon re-exposure to allergens and infection, and to the efficacy of Treg cell therapies. Much is known about how Treg cells develop, but we have lacked a framework for understanding how Treg responses are maintained. Our recent work has begun to reshape our thinking about how long-lived Treg responses are organised. We have found that long-term maintenance of Treg populations is dependent upon the presence of a subset of functionally quiescent cells marked by high levels of Bach2 expression (**Fig. 2**; Grant, Yang et al., J Exp Med 2020). We are developing new tools to understand how long-lived immunoregulatory and immunosuppressive Treg responses are maintained and establishing clinical collaborations to determine the consequences of this for inflammatory and allergic diseases and cancer.
@@ -39,7 +39,7 @@ T cell responses are clonally expanded from small numbers of antigen-specific na
 
 We have a long-standing interest in T cell memory. We conducted one of the earliest multiplexed single-cell gene expression analyses of immune cells revealing unappreciated heterogeneity in memory CD8+ T responses to vaccination (PNAS 2011). We defined transcriptional and epigenetic programmes of vaccine-induced memory T cells (Vaccine 2015, Cell Mol Immunol 2015). We defined molecular mechanisms by which long-lived memory CD8+ T cell responses to viral infection are maintained (Nat Immunol 2016).  We showed that long-term maintenance of Treg populations is dependent upon the presence of a subset of functionally quiescent cells marked by high levels of Bach2 expression (J Exp Med 2020). We have contributed to work showing that inhibition of AKT signalling enables expansion of T cells with a long-lived memory phenotype which mediates superior **adoptive immunotherapy responses** upon transfer into tumour-bearing recipients (Cancer Res, 2015), and that memory T cell–driven differentiation of naive cells impairs adoptive immunotherapy (J Clin Invest, 2015).
 
-### Molecular and cellular mechanisms of tumour immunosuppression 
+#### Molecular and cellular mechanisms of tumour immunosuppression 
 
 Cancers adapt to their immune environment to evade attack. According to the **cancer immunoediting** hypothesis, tumour development is characterized by an initial ‘elimination’ phase, during which a majority of cancer cells are destroyed by components of innate and adaptive immunity (**Fig. 3**). This is followed by an ‘equilibrium’ phase, during which pressure from the immune system contributes to evolutionary selection of tumour escape variants that give rise to an ‘escape’ phase characterized by evasion from immune control and unrestrained tumour growth.