Priyadharshini Devarajan

Autoimmune effector memory T cells: the bad and the good

Immunological memory is a hallmark of adaptive immunity, a defense mechanism endowed to vertebrates during evolution. However, an autoimmune pathogenic role of memory lymphocytes is also emerging with accumulating evidence, despite reasonable skepticism on their existence in a chronic setting of autoimmune damage. It is conceivable that autoimmune memory would be particularly harmful since memory cells would constantly “remember” and attack the body’s healthy tissues. It is even more detrimental given the resistance of memory T cells to immunomodulatory therapies. In this review, we focus on self-antigen-reactive CD4+ effector memory T (TEM) cells, surveying the evidence for the role of the TEM compartment in autoimmune pathogenesis. We will also discuss the role of TEM cells in chronic and acute infectious disease settings and how they compare to their counterparts in autoimmune diseases. With their long-lasting potency, the autoimmune TEM cells could also play a critical role in anti-tumor immunity, which may be largely based on their reactivity to self-antigens. Therefore, although autoimmune TEM cells are “bad” due to their role in relentless perpetration of tissue damage in autoimmune disease settings, they are unlikely a by-product of industrial development along the modern surge of autoimmune disease prevalence. Rather, they may be a product of evolution for their “good” in clearing damaged host cells in chronic infections and malignant cells in cancer settings.

Autoimmunity‐mediated antitumor immunity: Tumor as an immunoprivileged self

The association of autoimmunity with antitumor immunity challenges a paradigm of selective surveillance against tumors. Aided with well‐characterized models of robust autoimmunity, we show that self‐antigen‐specific effector T (Teff) cell clones could eradicate tumor cells. However, a tumor microenvironment reinforced by Treg cells and myeloid‐derived suppressor cells (MDSCs) presented a barrier to the autoimmune effectors, more so in tumors than in healthy tissues. This barrier required optimal CTLA4 expression in Teff cells. In a spontaneous model of breast cancer, subtle reductions in CTLA4 expression impeded tumor onset and progression, providing the first direct evidence that CTLA4 inhibits spontaneous tumor development. In an adoptive therapy model of lymphoma, self‐antigen‐specific Teff cells were potentiated by even a modest reduction of CTLA4. A subtle reduction of CTLA4 did not curtail Treg‐cell suppression. Thus, Teff cells had an exquisite sensitivity to physiological levels of CTLA4 variations. However, both Treg and Teff cells were impacted by anti‐CTLA4 antibody blockade. Therefore, whether CTLA4 impacts through Treg cells or Teff cells depends on its expression level. Overall, the results suggest that the tumor microenvironment represents an “immunoprivileged self” that could be overcome practically and at least partially by RNAi silencing of CTLA4 in Teff cells.

Loss of Mpzl3 Function Causes Various Skin Abnormalities and Greatly Reduced Adipose Depots

The rough coat (rc) spontaneous mutation causes sebaceous gland hypertrophy, hair loss and extracutaneous abnormalities including growth retardation. The rc mice have a missense mutation in the predicted immunoglobulin protein Mpzl3. In this study, we generated Mpzl3 knockout mice to determine its functions in the skin. Homozygous Mpzl3 knockout mice showed unkempt and greasy hair coat and hair loss soon after birth. Histological analysis revealed severe sebaceous gland hypertrophy and increased dermal thickness, but did not detect significant changes in the hair cycle. Mpzl3 null mice frequently developed inflammatory skin lesions; however, the early onset skin abnormalities were not the results of immune defects. The abnormalities in the Mpzl3 knockout mice resemble closely those observed in the rc/rc mice, as well as mice heterozygous for both the rc and Mpzl3 knockout alleles, indicating that rc and Mpzl3 are allelic. Using a lacZ reporter gene, we detected Mpzl3 promoter activity in the companion layer and inner root sheath of the hair follicle, sebaceous gland, and epidermis. Loss of MPZL3 function also caused a striking reduction in cutaneous and overall adipose tissue. These data reveal a complex role for Mpzl3 in the control of skin development, hair growth and adipose cell functions.

Opposing Effects of CTLA4 Insufficiency on Regulatory versus Conventional T Cells in Autoimmunity Converge on Effector Memory in Target Tissue

Quantitative variations in CTLA4 expression, because of genetic polymorphisms, are associated with various human autoimmune conditions, including type 1 diabetes (T1D). Extensive studies have demonstrated that CTLA4 is not only essential for the suppressive role of regulatory T cells (Treg) but also required for intrinsic control of conventional T (Tconv) cells. We report that a modest insufficiency of CTLA4 in mice, which mimics the effect of some human CTLA4 genetic polymorphisms, accompanied by a T1D-permissive MHC locus, was sufficient to induce juvenile-onset diabetes on an otherwise T1D-resistant genetic background. Reduction in CTLA4 levels had an unanticipated effect in promoting Treg function both in vivo and in vitro. It led to an increase in Treg memory in both lymphoid and nonlymphoid target tissue. Conversely, modulating CTLA4 by either RNA interference or Ab blockade promoted conventional effector memory T cell formation in the Tconv compartment. The CD4+ conventional effector memory T cells, including those within target tissue, produced IL-17 or IFN-γ. Blocking IL-7 signaling reduced the Th17 autoimmune compartment but did not suppress the T1D induced by CTLA4 insufficiency. Enhanced effector memory formation in both Tconv and Treg lineages may underpin the apparently dichotomized impact of CTLA4 insufficiency on autoimmune pathogenesis. Therefore, although the presence of CTLA4 plays a critical role in controlling homeostasis of T cells, its quantitative variation may impose diverse or even opposing effects on distinct lineages of T cells, an optimal sum of which is necessary for preservation of T cell immunity while suppressing tissue damage.

The immunological identity of tumor Self implications

By means of well-characterized autoimmunity models, we comparatively probed the “selfness” of malignant cells and their normal counterparts. We found that tumors activate self-tolerance mechanisms much more efficiently than normal tissues, reflecting a status of immunoprivileged “self.” Our findings indicate that potent autoimmune responses can eradicate established malignancies, yet the collateral destruction of healthy tissues may prove difficult to circumvent.

Initiation of inflammatory tumorigenesis by CTLA4 insufficiency due to type 2 cytokines

Genetically predisposed CTLA4 insufficiency in humans is associated with gastric cancer development, which is paradoxical to the prototypical role of CTLA4 in suppressing antitumor immunity. CTLA4 is a critical immune checkpoint against autoimmune disorders. Autoimmunity has been implicated in protumor or antitumor activities. Here, we show that CTLA4 insufficiency initiates de novo tumorigenesis in the mouse stomach through inflammation triggered by host-intrinsic immune dysregulation rather than microbiota, with age-associated progression to malignancy accompanied by epigenetic dysregulation. The inflammatory tumorigenesis required CD4 T cells, but not the TH1 or TH17 subsets. Deficiencies in IL-4 and IL-13 or IL-4 receptor &agr; broke the link between inflammation and initiation of tumorigenesis. This study establishes the causality of CTLA4 insufficiency in gastric cancer and uncovers a role of type 2 inflammation in initiating gastric epithelial transformation. These findings suggest possible improvement of immune therapies by blocking tumorigenic type 2 inflammation while preserving antitumor type 1 immunity.