A challenging case of recurrent idiopathic hemophagocytic lymphohistiocytosis (HLH) initially presenting in an infant with Pneumocystis jirovecii pneumonia
SPRINGER/PLENUM PUBLISHERS. 2021: S55
View details for Web of Science ID 000639851600094
T Cell Proliferation and Colitis Are Initiated by Defined Intestinal Microbes.
Journal of immunology (Baltimore, Md. : 1950)
2018; 201 (1): 243–50
Inflammatory bowel disease has been associated with the dysregulation of T cells specific to Ags derived from the intestinal microbiota. How microbiota-specific T cells are regulated is not completely clear but is believed to be mediated by a combination of IgA, regulatory T cells, and type 3 innate lymphoid cells. To test the role of these regulatory components on microbiota-specific T cells, we bred CBir1 TCR transgenic (CBir1Tg) mice (specific to flagellin from common intestinal bacteria) onto a lymphopenic Rag1-/- background. Surprisingly, T cells from CBir1Tg mice bred onto a Rag1-/- background could not induce colitis and did not differentiate to become effectors under lymphopenic conditions, despite deficits in immunoregulatory factors, such as IgA, regulatory T cells, and type 3 innate lymphoid cells. In fact, upon transfer of conventional CBir1Tg T cells into lymphopenic mice, the vast majority of proliferating T cells responded to Ags other than CBir1 flagellin, including those found on other bacteria, such as Helicobacter spp. Thus, we discovered a caveat in the CBir1Tg model within our animal facility that illustrates the limitations of using TCR transgenics at mucosal surfaces, where multiple TCR specificities can respond to the plethora of foreign Ags. Our findings also indicate that T cell specificity to the microbiota alone is not sufficient to induce T cell activation and colitis. Instead, other interrelated factors, such as the composition and ecology of the intestinal microbiota and host access to Ag, are paramount in controlling the activation of microbiota-specific T cell clones.
View details for DOI 10.4049/jimmunol.1800236
View details for PubMedID 29777027
View details for PubMedCentralID PMC6082663
The ability to rearrange dual TCRs enhances positive selection, leading to increased Allo- and Autoreactive T cell repertoires.
Journal of immunology (Baltimore, Md. : 1950)
2014; 193 (4): 1778–86
Thymic selection is designed to ensure TCR reactivity to foreign Ags presented by self-MHC while minimizing reactivity to self-Ags. We hypothesized that the repertoire of T cells with unwanted specificities such as alloreactivity or autoreactivity are a consequence of simultaneous rearrangement of both TCRα loci. We hypothesized that this process helps maximize production of thymocytes capable of successfully completing thymic selection, but results in secondary TCRs that escape stringent selection. In T cells expressing two TCRs, one TCR can mediate positive selection and mask secondary TCR from negative selection. Examination of mice heterozygous for TRAC (TCRα(+/-)), capable of only one functional TCRα rearrangement, demonstrated a defect in generating mature T cells attributable to decreased positive selection. Elimination of secondary TCRs did not broadly alter the peripheral T cell compartment, though deep sequencing of TCRα repertoires of dual TCR T cells and TCRα(+/-) T cells demonstrated unique TCRs in the presence of secondary rearrangements. The functional impact of secondary TCRs on the naive peripheral repertoire was evidenced by reduced frequencies of T cells responding to autoantigen and alloantigen peptide-MHC tetramers in TCRα(+/-) mice. T cell populations with secondary TCRs had significantly increased ability to respond to altered peptide ligands related to their allogeneic ligand as compared with TCRα(+/-) cells, suggesting increased breadth in peptide recognition may be a mechanism for their reactivity. Our results imply that the role of secondary TCRs in forming the T cell repertoire is perhaps more significant than what has been assumed.
View details for DOI 10.4049/jimmunol.1400532
View details for PubMedID 25015825
View details for PubMedCentralID PMC4119549
T-cell selection and intestinal homeostasis.
2014; 259 (1): 60–74
Although intestinal bacteria live deep within the body, they are topographically on the exterior surface and thus outside the host. According to the classic notion that the immune system targets non-self rather than self, these intestinal bacteria should be considered foreign and therefore attacked and eliminated. While this appears to be true for some commensal bacterial species, recent data suggest that the immune system actively becomes tolerant to many bacterial organisms. The induction or activation of regulatory T (Treg) cells that inhibit, rather than promote, inflammatory responses to commensal bacteria appears to be a central component of mucosal tolerance. Loss of this mechanism can lead to inappropriate immune reactivity toward commensal organisms, perhaps contributing to mucosal inflammation characteristic of disorders such as inflammatory bowel disease.
View details for DOI 10.1111/imr.12171
View details for PubMedID 24712459
View details for PubMedCentralID PMC4028094
T cell immunodominance is dictated by the positively selecting self-peptide.
2014; 3: e01457
Naive T cell precursor frequency determines the magnitude of immunodominance. While a broad T cell repertoire requires diverse positively selecting self-peptides, how a single positively selecting ligand influences naive T cell precursor frequency remains undefined. We generated a transgenic mouse expressing a naturally occurring self-peptide, gp250, that positively selects an MCC-specific TCR, AND, as the only MHC class II I-E(k) ligand to study the MCC highly organized immunodominance hierarchy. The single gp250/I-E(k) ligand greatly enhanced MCC-tetramer(+) CD4(+) T cells, and skewed MCC-tetramer(+) population toward V11α(+)Vβ3(+), a major TCR pair in MCC-specific immunodominance. The gp250-selected V11α(+)Vβ3(+) CD4(+) T cells had a significantly increased frequency of conserved MCC-preferred CDR3 features. Our studies establish a direct and causal relationship between a selecting self-peptide and the specificity of the selected TCRs. Thus, an immunodominant T cell response can be due to a dominant positively selecting self-peptide. DOI: http://dx.doi.org/10.7554/eLife.01457.001.
View details for DOI 10.7554/eLife.01457
View details for PubMedID 24424413
View details for PubMedCentralID PMC3885792
Neuropilin-1 attenuates autoreactivity in experimental autoimmune encephalomyelitis.
Proceedings of the National Academy of Sciences of the United States of America
2011; 108 (5): 2040–45
Neuropilin-1 (Nrp1) is a cell surface molecule originally identified for its role in neuronal development. Recently, Nrp1 has been implicated in several aspects of immune function including maintenance of the immune synapse and development of regulatory T (T(reg)) cells. In this study, we provide evidence for a central role of Nrp1 in the regulation of CD4 T-cell immune responses in experimental autoimmune encephalitis (EAE). EAE serves as an animal model for the central nervous system (CNS) inflammatory disorder multiple sclerosis (MS). EAE is mediated primarily by CD4(+) T cells that migrate to the CNS and mount an inflammatory attack against myelin components, resulting in CNS pathology. Using a tissue-specific deletion system, we observed that the lack of Nrp1 on CD4(+) T cells results in increased EAE severity. These conditional knockout mice exhibit preferential T(H)-17 lineage commitment and decreased T(reg)-cell functionality. Conversely, CD4(+) T cells expressing Nrp1 suppress effector T-cell proliferation and cytokine production both in vivo and in vitro independent of T(reg) cells. Nrp1-mediated suppression can be inhibited by TGF-β blockade but not by IL-10 blockade. These results suggest that Nrp1 is essential for proper maintenance of peripheral tolerance and its absence can result in unchecked autoreactive responses, leading to diseases like EAE and potentially MS.
View details for DOI 10.1073/pnas.1008721108
View details for PubMedID 21245328
View details for PubMedCentralID PMC3033275
The AP-1 transcription factor Batf controls T(H)17 differentiation.
2009; 460 (7253): 405–9
Activator protein 1 (AP-1, also known as JUN) transcription factors are dimers of JUN, FOS, MAF and activating transcription factor (ATF) family proteins characterized by basic region and leucine zipper domains. Many AP-1 proteins contain defined transcriptional activation domains, but BATF and the closely related BATF3 (refs 2, 3) contain only a basic region and leucine zipper, and are considered to be inhibitors of AP-1 activity. Here we show that Batf is required for the differentiation of IL17-producing T helper (T(H)17) cells. T(H)17 cells comprise a CD4(+) T-cell subset that coordinates inflammatory responses in host defence but is pathogenic in autoimmunity. Batf(-/-) mice have normal T(H)1 and T(H)2 differentiation, but show a defect in T(H)17 differentiation, and are resistant to experimental autoimmune encephalomyelitis. Batf(-/-) T cells fail to induce known factors required for T(H)17 differentiation, such as RORgamma t (encoded by Rorc) and the cytokine IL21 (refs 14-17). Neither the addition of IL21 nor the overexpression of RORgamma t fully restores IL17 production in Batf(-/-) T cells. The Il17 promoter is BATF-responsive, and after T(H)17 differentiation, BATF binds conserved intergenic elements in the Il17a-Il17f locus and to the Il17, Il21 and Il22 (ref. 18) promoters. These results demonstrate that the AP-1 protein BATF has a critical role in T(H)17 differentiation.
View details for DOI 10.1038/nature08114
View details for PubMedID 19578362
View details for PubMedCentralID PMC2716014
Tpl2 kinase regulates T cell interferon-gamma production and host resistance to Toxoplasma gondii
JOURNAL OF EXPERIMENTAL MEDICINE
2008; 205 (12): 2803-2812
Tpl2 (Tumor progression locus 2), also known as Cot/MAP3K8, is a hematopoietically expressed serine-threonine kinase. Tpl2 is known to have critical functions in innate immunity in regulating tumor necrosis factor-alpha, Toll-like receptor, and G protein-coupled receptor signaling; however, our understanding of its physiological role in T cells is limited. We investigated the potential roles of Tpl2 in T cells and found that it was induced by interleukin-12 in human and mouse T cells in a Stat4-dependent manner. Deficiency of Tpl2 was associated with impaired interferon (IFN)-gamma production. Accordingly, Tpl2(-/-) mice had impaired host defense against Toxoplasma gondii with reduced parasite clearance and decreased IFN-gamma production. Furthermore, reconstitution of Rag2(-/-) mice with Tpl2-deficient T cells followed by T. gondii infection recapitulated the IFN-gamma defect seen in the Tpl2-deficient mice, confirming a T cell-intrinsic defect. CD4(+) T cells isolated from Tpl2(-/-) mice showed poor induction of T-bet and failure to up-regulate Stat4 protein, which is associated with impaired TCR-dependent extracellular signal-regulated kinase activation. These data underscore the role of Tpl2 as a regulator of T helper cell lineage decisions and demonstrate that Tpl2 has an important functional role in the regulation of Th1 responses.
View details for DOI 10.1084/jem.20081461
View details for Web of Science ID 000261295300014
View details for PubMedID 19001140
View details for PubMedCentralID PMC2585846