AN IL-12 FAMILY HETERODIMER THAT REGULATES IL-4 PRODUCTION BY T CELLS - SUMMARY: AN IL-12 FAMILY HETERODIME…

Assistance award details

Assistance award identifier

ASST_NON_R21AI166330_075

FAIN

R21AI166330

Recipient

UNIVERSITY OF MARYLAND, BALTIMORE

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.855

Total obligated

$424,875

Period

Sep 24, 2021 – Aug 31, 2023

Fiscal year

2021

Place of performance state

MD

Source file

FY2021_All_Assistance_Full_20261006.zip

Description

AN IL-12 FAMILY HETERODIMER THAT REGULATES IL-4 PRODUCTION BY T CELLS - SUMMARY: AN IL-12 FAMILY HETERODIMER THAT REGULATES IL-4 PRODUCTION BY T CELLS THE IMMUNE SYSTEM TAILORS EFFECTOR RESPONSES TO MATCH BOTH SPECIFIC PATHOGENS AS WELL AS THE TISSUES THEY INFECT. IN THIS CONTEXT, A PAIR OF CYTOKINES (IL-12 AND IL-23) PRODUCED BY INNATE CELLS EARLY IN AN INFECTION PLAY AN IMPORTANT ROLE. IL-12 DRIVES THE DIFFERENTIATION OF T CELLS TOWARDS IFN PRODUCING EFFECTORS WHILE IL-23 PROMOTES IL-17 RESPONSES. BOTH IL-12 AND IL-23 ARE HETERODIMERS WHICH SHARE A COMMON SUBUNIT (IL-12P40) BUT DIFFER IN THE 2ND SUBUNIT (IL-12P35 FOR IL-12 AND IL- 23P19 FOR IL-23). THE SIGNIFICANCE OF THIS PROPOSAL IS THAT WE IDENTIFY A NEW INNATE CYTOKINE IN THIS FAMILY, WHICH PROMOTES THE DIFFERENTIATION OF IL-4 AND IL-10 PRODUCING T CELLS. THIS NEW HETERODIMERIC CYTOKINE ALSO USES THE IL-12P40 SUBUNIT, BUT BINDS A DISTINCT PARTNER FROM THE OTHER PROTEINS, A SECRETED CD5-LIKE ANTIGEN CALLED CD5L. IN THIS PROPOSAL, WE WILL EXAMINE THE MECHANISMS BY WHICH P40+CD5L EXERTS ITS IL-4/IL-10 PROMOTING ACTIVITY, USING NEW RECOMBINANT PROTEINS, SPECIFICALLY DEVELOPED MONOCLONAL ANTIBODIES AND AVAILABLE KNOCKOUT MICE. ACCORDINGLY, THE FOLLOWING SPECIFIC AIMS WILL EVALUATE OUR CENTRAL HYPOTHESIS THAT “A HETERODIMER FORMED BY IL-12P40 PLUS CD5L FUNCTIONS AS AN INNATE CYTOKINE AND AMPLIFIES IL-4 AND IL-10 PRODUCTION BY LYMPHOCYTES IN VIVO”. IN SPECIFIC AIM 1 WE CHARACTERIZE THE DIFFERENT LINEAGES OF IMMUNE CELLS (INCLUDING T, B, NKT, ILCS, MACROPHAGES, ETC.) WHICH RESPOND TO P40+CD5L IN VIVO. WE WILL THEN EVALUATE THE CELLULAR RECEPTORS INVOLVED IN SENSING P40+CD5L AND THE MAJOR SIGNALING PATHWAYS DOWNSTREAM OF THESE RECEPTORS IN ACTIVATED T CELLS. FINALLY, WE WILL PERFORM UNBIASED TRANSCRIPTOMIC ANALYSIS TO IDENTIFY THE GLOBAL IMPACT OF P40+CD5L. IN THE SECOND AIM, WE WILL USE INFECTION AND TUMOR MODELS, EXPLOITING NATURAL VARIATION OF P40+CD5L LEVELS IN DIFFERENT MOUSE STRAINS TO PINPOINT ITS ROLE IN TW