Selected Publications

1. Sieling PA, Jullien D, Dahlem M, Tedder T, Rea TH, Modlin RL, Porcelli SA. CD1 expression in human leprosy lesions: Correlation with effective cellular immunity. J Immunol 162:1851-1858, 1999.

2. Sieling PA, Ochoa M, Jullien D, Leslie DS, Sabet S, Rosat J, Burdick AE, Rea TH, Brenner MB, Porcelli SA, Modlin RL. Evidence for human CD4+ T Cells in the CD1-restricted repertoire: Derivation of mycobacteria-reactive T cells from leprosy lesions. J Immunol 164:4790-4796, 2000.

3. Sieling PA, Porcelli SA, Duong BT, Spada F, Bloom BR, Diamond B, Hahn BH. Human double-negative T cells in systemic lupus erythematosus provide help for IgG and are restricted by CD1c. J Immunol 165:5338-44, 2000.

4. Ochoa MT†, Stenger S†, Sieling PA†, Thoma-Uszynski S, Sabet S, Cho S, Krensky AM, Rollinghoff M, Sarno EN, Burdick A, Rea TH, Modlin RL. A role for the antimicrobial protein granulysin in host defense in leprosy. †These authors contributed equally to this work. Nature Medicine. 7:174-179, 2001.

5. Sieling PA, Chung W, Duong BT, Godowski PJ, Modlin RL. Toll-like receptor 2 ligands as adjuvants for human Th1 responses. J Immunol 170:194-200, 2003.

6. Ochoa MT, Legaspi AJ, Hatziris Z, Godowski PJ, Modlin RL, Sieling PA. Distribution of Toll-like receptor 1 and Toll-like receptor 2 in human lymphoid tissue. Immunology 108:10-15, 2003.

Research Interests

The overall research objectives in my laboratory are to identify basic mechanisms of innate and adaptive immunity to infection. One major research project concerns identifying mechanisms whereby dendritic cells (innate immune system) activate T cells (adaptive). Dendritic cells express pattern recognition receptors that allow the cells to recognize conserved microbial structures. Recognition of microbial patterns by pattern recognition receptors, in particular Toll-like receptors (TLRs) activates both direct antimicrobial activity and indirectly modulates the adaptive immune response of B and T cells. TLR1 and TLR2 combine to form a pattern recognition molecule for microbial lipoproteins. We found that TLR1 and TLR2 are coexpressed on dendritic cells in lymphoid tissue. The coexpression of TLR1 and TLR2 on dendritic cells provides the host with the ability to respond to a variety of microbial ligands at sites conducive to the generation of an immune response. We have also found that bacterial lipopeptides stimulate T helper 1 responses in an accessory cell-dependent manner in vitro. We are currently investigating the mechanism of adjuvant activity of TLR ligands and identifying the T cell subset that is responsive to TLR ligands.

The second major research topic of the laboratory is to define the role of T cells in response to infection. We have investigated the role of CD1-restricted T cells in mycobacterial disease for the past ten years. CD1 is an antigen presentation pathway similar to major histocompatibility (MHC) antigen presentation, but with a major distinction, that is the presentation of lipid antigens in contrast to the peptide antigens presented by MHC. We have identified glycolipid antigens of mycobacteria that activate CD1-restricted T cells and provided evidence suggesting that CD1-restricted T cells contribute to immune responses that limit mycobacterial infections. Currently we are investigating the precise chemical structures of the glycolipid antigens that activate CD1-restricted T cells. We are also expanding our investigations of CD1-restricted T cells to characterize their activity against non-mycobacterial human pathogens.

A third major area of investigation is to determine the mechanism of T cell help for autoantibody production in systemic lupus erythematosus (SLE). The ability of T cells to provide help to B cells depends on their recognition of appropriately presented antigen on the surface of B cells. We have found that CD4-, CD8- double negative (DN) T cells in SLE patients promote IgG production in a CD1c-restricted manner, whereas DN T cells of healthy donors exhibited weak helper activity. Our data suggest that CD1c-restricted T cells from SLE patients can provide help to CD1c-expressing B cells for IgG production and could therefore promote pathogenic autoantibody responses in SLE.