Studies of T cell activation of normal murine T cell clones of the TH1 type have shown that two signals are required to stimulate the cells to make interleukin-2 (IL-2) and divide. One signal is given through the antigen- specific receptor that is uniquely expressed on each clone. The other signal is called costimulation and is delivered through a different receptor that has not yet been characterized. Signal 1 in the absence of signal 2 induces a state of hyporesponsiveness in the T cell clone known as clonal anergy. In this state, the cell fails to make significant amounts of IL-2 when restimulated with both signals 1 and 2. During the past year we have made progress in two areas. First, we have shown that the anergic state can be reversed in T cell clones by stimulating the cells with IL-2. This reversal occurs in all the cells and affects all impaired lymphokine production. Anergy was also found to dissipate spontaneously, although much more slowly, in the absence of IL-2 stimulation. Finally, we showed that a partial state of anergy could be induced by normal activation with antigen and APC provided that IL-2 and possibly other factors were removed from the culture medium by washing the cells. The results demonstrate that the anergic state is not a permanent change in the TH1 cell. They also indicate that anergy induction might be a consequence of the inability of the cell to divide following stimulation. Thus, costimulation may only be required in normal activation to produce IL-2, which in turn prevents anergy by driving the cell through repeated rounds of division. In a separate set of experiments, we demonstrated that costimulation is required in order to make murine TH1 clones competent to proliferate in response to interleukin-4. Induction of anergy in the cells blocked this ability to become competent in parallel with the impairment of the cells to make IL-2; however, IL-2 stimulation was not the only signal required to gain competence, because addition of IL-2 to a T cell-receptor occupancy signal, mediated by concanavalin A, only allowed the cells to become partially competent to respond to IL-4. We concluded from these experiments that costimulatory signals contribute directly to the attainment of full competence to respond to IL-4.
| Johnson, Andy L; Aravind, L; Shulzhenko, Natalia et al. (2009) Themis is a member of a new metazoan gene family and is required for the completion of thymocyte positive selection. Nat Immunol 10:831-9 |
| Singh, Nevil J; Cox, Maureen; Schwartz, Ronald H (2007) TLR ligands differentially modulate T cell responses to acute and chronic antigen presentation. J Immunol 179:7999-8008 |
| Choi, Seeyoung; Schwartz, Ronald H (2007) Molecular mechanisms for adaptive tolerance and other T cell anergy models. Semin Immunol 19:140-52 |
| Singh, Nevil J; Schwartz, Ronald H (2006) Primer: mechanisms of immunologic tolerance. Nat Clin Pract Rheumatol 2:44-52 |
| Singh, Nevil J; Schwartz, Ronald H (2006) The lymphopenic mouse in immunology: from patron to pariah. Immunity 25:851-5 |
| Chiodetti, Lynda; Choi, Seeyoung; Barber, Daniel L et al. (2006) Adaptive tolerance and clonal anergy are distinct biochemical states. J Immunol 176:2279-91 |
| Singh, Nevil J; Chen, Chuan; Schwartz, Ronald H (2006) The impact of T cell intrinsic antigen adaptation on peripheral immune tolerance. PLoS Biol 4:e340 |
| Choi, Heonsik; Cho, Sung-Yup; Schwartz, Ronald H et al. (2006) Dual effects of Sprouty1 on TCR signaling depending on the differentiation state of the T cell. J Immunol 176:6034-45 |
| Safford, Meredith; Collins, Samuel; Lutz, Michael A et al. (2005) Egr-2 and Egr-3 are negative regulators of T cell activation. Nat Immunol 6:472-80 |
| Cho, Eun-Gyung; Schwartz, Ronald H; Kim, Moon G (2005) Shedding of membrane epithin is blocked without LDLRA4 and its protease activation site. Biochem Biophys Res Commun 327:328-34 |
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